Posterior segment drug delivery

ABSTRACT

A therapeutic device to release a therapeutic agent comprises a porous structure coupled to a container comprising a reservoir. The reservoir comprises a volume sized to release therapeutic amounts of the therapeutic agent for an extended time when coupled to the porous structure and implanted in the patient. The porous structure may comprise a first side coupled to the reservoir and a second side to couple to the patient to release the therapeutic agent. A plurality of interconnecting channels can extend from the first side to the second side so as to connect a first a plurality of openings on the first side with a second plurality of openings on the second side. Each of the openings on the first side can be connected to each of the openings on the second side with the plurality of interconnecting channels, such that the rate of release of the therapeutic agent can be substantially maintained when one or more of the openings is blocked, for example with particles, cells, bacteria or tissue when the device is implanted for an extended time. The length of the channels extending from the first side to the second side may comprise an effective length greater than a distance across the porous structure from the first side to the second side. The therapeutic device many comprise an expandable retention structure and an expandable reservoir, such that the device can be delivered from a lumen of a delivery device and expand when positioned in the patient. The therapeutic device may comprises a penetrable barrier to inject therapeutic agent into the device when implanted in the patient.

CROSS-REFERENCES TO RELATED APPLICATIONS

The present application claims the benefit under 35 USC 119(e) of U.S.Provisional Application Nos. 61/148,375 filed Jan. 29, 2009, entitled,“POSTERIOR SEGMENT DRUG DELIVERY”; 61/174,887 filed May 1, 2009,entitled “POSTERIOR SEGMENT DRUG DELIVERY”; 61/261,717 filed Nov. 16,2009, entitled “POSTERIOR SEGMENT DRUG DELIVERY”; and 61/284,832 filedon Dec. 24, 2009, entitled “POSTERIOR SEGMENT DRUG DELIVERY”; and61/299,282 filed Jan. 28, 2010, entitled “POSTERIOR SEGMENT DRUGDELIVERY”; the full disclosures of which are incorporated herein byreference.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

NOT APPLICABLE

BACKGROUND OF THE INVENTION

The present invention relates to delivery of therapeutic agents to theposterior segment of the eye. Although specific reference is made to thedelivery of macromolecules comprising antibodies or antibody fragmentsto the posterior segment of the eye, embodiments of the presentinvention can be used to deliver many therapeutic agents to many tissuesof the body. For example, embodiments of the present invention can beused to deliver therapeutic agent to one or more of the followingtissues: intravascular, intra-articular, intrathecal, pericardial,intraluminal and gut.

The eye is critical for vision. The eye has a cornea and a lens thatform an image on the retina. The image formed on the retina is detectedby rods and cones on the retina. The light detected by the rods andcones of the retina is transmitted to the occipital cortex brain via theoptic nerve, such that the individual can see the image formed on theretina. Visual acuity is related to the density of rods and cones on theretina. The retina comprises a macula that has a high density of cones,such that the user can perceive color images with high visual acuity.

Unfortunately, diseases can affect vision. In some instances the diseaseaffecting vision can cause damage to the retina, even blindness in atleast some instances. One example of a disease that can affect vision isage-related macular degeneration (hereinafter AMD). Although therapeuticdrugs are known that can be provided to minimize degradation of theretina, in at least some instances the delivery of these drugs can beless than ideal.

In some instances a drug is injected into the eye through the sclera.One promising class of drugs for the treatment of AMD is known asvascular endothelial growth factor VEGF inhibitors. Unfortunately, in atleast some instances injection of drugs can be painful for the patient,involve at least some risk of infection and hemorrhage and retinaldetachment, and can be time consuming for the physician and patient.Consequently, in at least some instances the drug may be delivered lessoften than would be ideal, such that at least some patients may receiveless drug than would be ideal in at least some instances.

Work in relation to embodiments of the present invention also suggeststhat an injection of the drug with a needle results in a bolus deliveryof the drug, which may be less than ideal in at least some instances.For example, with a bolus injection of drug, the concentration of drugin the vitreous humor of the patient may peak at several times therequired therapeutic amount, and then decrease to below the therapeuticamount before the next injection.

Although some implant devices have been proposed, many of the knowndevices are deficient in at least some respects in at least someinstances. At least some of the known implanted devices do not providesustained release of a therapeutic drug for an extended period. Forexample, at least some of the known implanted devices may rely onpolymer membranes or polymer matrices to control the rate of drugrelease, and many of the known membranes and matrices may beincompatible with at least some therapeutic agents such as ionic drugsand large molecular weight protein drugs in at least some instances. Atleast some of the known semi-permeable polymer membranes may havepermeability that is less than ideal for the extended release of largemolecular weight proteins such as antibodies or antibody fragments.Also, work in relation to embodiments of the present invention alsosuggests that at least some of the known semi-permeable membranes canhave a permeability of large molecules that may vary over time and atleast some of the known semi-permeable membranes can be somewhatfragile, such that drug release for extended periods can be less thanideal in at least some instances. Although capillary tubes have beensuggested for drug release, work in relation to embodiments of thepresent invention suggests that flow through capillary tubes can be lessthan ideal in at least some instances, for example possibly due tobubble formation and partial clogging.

At least some of the known implantable devices can result in patientside effects in at least some instances when a sufficient amount of drugis delivered to treat a condition of the eye. For example, at least someof the commercially available small molecule drug delivery devices mayresult in patient side effects such as cataracts, elevated intraocularpressure, dizziness or blurred vision in at least some instances.Although corticosteroids and analogues thereof may be delivered with animplanted device to treat inflammation, the drug delivery profile can beless than ideal such that the patient may develop a cataract in at leastsome instances.

Although at least some of the proposed implanted devices may permit aninjection into the device, one potential problem is that an injectioninto an implanted device can cause at least some risk of infection forthe patient in at least some instances. Also, in at least some instancesthe drug release rate of an implanted device can change over time, suchthat the release rate of the drug can be less than ideal after injectionin at least some instance. At least some of the proposed implanteddevices may not be implanted so as to minimize the risk of infection tothe patient. For example, at least some of the proposed devices thatrely on pores and capillaries may allow microbes such as bacteria topass through the capillary and/or pore, such that infection may bespread in at least some instances. Also, work in relation to embodimentsof the present invention suggests that at least some of the proposedimplanted devices do not provide adequate protection from the patient'simmune system, such as from macrophages and antibodies, thereby limitingthe therapeutic effect in at least some instances.

In light of the above, it would be desirable to provide improvedtherapeutic devices and methods that overcome at least some of the abovedeficiencies of the known therapies, for example with improved drugrelease that can be maintained when implanted over an extended time.

SUMMARY OF THE INVENTION

Embodiments of the present invention provide therapeutic devices thatdeliver therapeutic amounts of a therapeutic agent for an extended timeto the posterior segment of the eye, for example an extended time of atleast about 1 month. The therapeutic device may reduce the frequency ofnegative side effects associated with direct intraocular injection suchas pain, retinal detachment, hemorrhaging and infection becauseinjections can be made less frequently and can be made into thereservoir of the device rather than into the eye. The therapeutic devicecan be configured to replace the therapeutic agent when the device isimplanted at least partially within the eye of the patient. Thetherapeutic device may be implanted in the eye so as to extend throughthe sclera of the eye, and the therapeutic device may comprise acontainer and a port or penetrable barrier configured to receive aquantity of therapeutic agent. The therapeutic agent can be placed inthe container in many ways, for example by placing a solid insertthrough the port to the inside of the container or by injecting aformulation of the therapeutic agent through the penetrable barrier intothe container. The therapeutic device may comprise a binding agent thatreversibly or releasably couples to the therapeutic agent such that thetherapeutic agent is released from the device for the extended time.

In many embodiments, the therapeutic device is configured to providecontinuous release of therapeutic quantities of at least one therapeuticagent for an extended time of at least 3 months, for example 6 months,such that the frequency of injections into the therapeutic device andrisk of infection can be substantially decreased. In additionalembodiments, the therapeutic device is configured to provide continuousrelease of therapeutic quantities of at least one therapeutic agent foran extended time of at least 12 months, or at least 2 years or at least3 years.

The therapeutic device can be configured in many ways to release thetherapeutic agent for the extended time and may comprise at least one ofan opening, an elongate structure, a porous structure, or a poroussurface sized to release the therapeutic agent for the extended time.For example, the therapeutic device may comprise the porous structure torelease the therapeutic agent through the porous structure for theextended period. The porous structure may comprise a sintered materialhaving many channels, for example interconnecting channels, extendingaround many particles adhered to each other. The porous structure maycomprise a first side comprising a first plurality of openings coupledto the reservoir and a second side comprising a second plurality ofopenings to couple to the vitreous humor. The interconnecting channelsmay extend between each of the first plurality of openings of the firstside and each of the second plurality of openings of the second side soas to maintain release of the therapeutic agent through the porousstructure, for example when at least some the openings are blocked. Theporous structure can be rigid and maintain release of the therapeuticagent through the interconnecting channels when tissue or cells cover atleast a portion of the openings, for example when the porous structureis implanted for an extended time and the drug reservoir refilled.

The therapeutic device may comprise a retention structure configured tocouple to the sclera to position the container for delivery of thetherapeutic agent into the vitreous humor of the eye, such that theconjunctiva may extend over the retention structure when the device isimplanted so as to inhibit the risk of infection to the patient andallow access to the device with decreased risk of infection. Forexample, the retention structure may comprise a flange extending outwardfor placement between the conjunctiva and sclera and a narrow portion tofit within the incision through the sclera. The narrow portion to fitthe incision may comprise an elongate cross sectional profile sized tofit the incision. The elongate cross-sectional profile sized to fit theincision can improve the fit of the implanted device to the scleralincision, and may seal the implant against the sclera along theincision. The elongate cross sectional profile of the narrow portion canbe sized in many ways to fit the incision. For example, the elongatecross section may comprises a first dimension longer than a seconddimension and may comprise one or more of many shapes such as dilatedslit, dilated slot, lentoid, oval, ovoid, or elliptical. The dilatedslit shape and dilated slot shape may correspond to the shape scleratissue assumes when cut and dilated. The lentoid shape may correspond toa biconvex lens shape. The elongate cross-section of the narrow portionmay comprise a first curve along an first axis and a second curve alonga second axis different than the first curve.

In many embodiments, the reservoir of the therapeutic device isflushable and/or refillable. This provides the added benefit that thephysician may remove the therapeutic agent from the patient by flushingthe agent from the reservoir of the therapeutic device rather thanwaiting for the therapeutic agent to be eliminated from the patient.This removal can be advantageous in cases where the patient has anadverse drug reaction or benefit from a pause in therapy sometimesreferred to as a drug holiday. The volume of the reservoir and releaserate of the porous structure can be tuned to receive a volume of acommercially available formulation, such that the therapeutic agent canbe released for an extended time. For example, the volume ofcommercially available therapeutic agent may correspond to a bolusinjection having a treatment duration, for example one month, and thereservoir volume and release rate tuned to receive the formulationvolume can extend the treatment duration of the injected volume by afactor of at least about two, for example from one month to two or moremonths.

The therapeutic device may comprise a first narrow profile configurationfor placement, and a second expanded profile to deliver the drug withthe reservoir when positioned in the eye. For example, the therapeuticdevice may comprise a flexible barrier material coupled to a support,such that the barrier material and support can be expanded from a firstnarrow profile configuration to the second expanded profileconfiguration. The support can provide a substantially constantreservoir volume in the expanded configuration, such that the device canbe tuned with the porous structure and expandable reservoir to receivethe volume of therapeutic agent formulation and so as to releasetherapeutic amounts for the extended time. The therapeutic device maycomprise a porous barrier extending around the container with channelssized to pass the therapeutic agent from the container therethrough andto inhibit migration of at least one of a bacterial cell out of thecontainer or a macrophage or other immune cell into the container.

In a first aspect, embodiments provide a therapeutic device to deliver atherapeutic agent to an eye having a sclera and a vitreous humor. Acontainer is configured to hold the therapeutic agent. The container isconfigured to release the therapeutic agent into the vitreous humor attherapeutic amounts for an extended time.

In many embodiments, the therapeutic agent comprises molecules having amolecular weight from about 100 Daltons to about 1,000,000 Daltons.

In many embodiments, the therapeutic agent comprises molecules having amolecular weight from about 200 Daltons to about 1000 Daltons.

In many embodiments, the therapeutic agent comprises a corticosteroid oran analogue thereof. The corticosteroid or the analogue thereof maycomprise one or more of trimacinalone, trimacinalone acetonide,dexamethasone, dexamethasone acetate, fluocinolone, fluocinoloneacetate, or analogues thereof.

In many embodiments, the therapeutic agent comprise a VEGF inhibitor.

In many embodiments, the therapeutic agent comprises a macromoleculehaving a molecular weight from about 10 k Daltons to about 400 kDaltons.

In many embodiments, the macromolecule may comprise a VEGF inhibitor.The macromolecule may comprise one or more of antibodies or antibodyfragments. The one or more of the antibodies or the antibody fragmentscomprise a VEGF inhibitor. The VEGF inhibitor may comprise Ranibizumab.The VEGF inhibitor may comprise Bevacizumab. The VEGF inhibitor maycomprise VEGF trap, for example Aflibercept™.

In many embodiments, the macromolecule comprise complement factor.

In many embodiments, the therapeutic agent comprise a complement factorinhibitor.

In many embodiments, container comprises a reservoir volume sized tocontain a liquid formulation of the therapeutic agent.

In many embodiments, the volume to contain the liquid formulation iswithin a range from 10 uL to about 100 uL.

In many embodiments, the container is sized to contain from about 0.001mg to about 50 mg of therapeutic agent, for example sized to containfrom about 0.1 mg to about 10 mg of therapeutic agent. The container maysized to contain from about 0.5 mg to about 1 mg of therapeutic agent.The container can be sized to contain from about 0.05 mg to about 1 mgof therapeutic agent.

In many embodiments, the container and the therapeutic agent areconfigured to release the therapeutic agent to sustain from about 0.1ug/mL to about 10 ug/mL of therapeutic agent in the vitreous humor forthe extended time. The container and the therapeutic agent can beconfigured to release the therapeutic agent to sustain from about 0.1ug/mL to about 4 ug/mL of the therapeutic agent in the vitreous humorfor the extended time. The container and the therapeutic agent can beconfigured to release the therapeutic agent to sustain from about 0.2ug/mL to about 5 ug/mL of the therapeutic agent in the vitreous humorfor the extended time.

In many embodiments, the extended time comprises at least about 1 month.For example, the extended time may comprise at least about 3 months. Theextended time may comprise at least about 6 months. The extended timemay comprise at least about 12 months. The extended time may comprise atleast about 18 months. The extended time may comprise at least about 24months.

In many embodiments, the therapeutic device further comprises a bindingagent to couple to the therapeutic agent such that the therapeutic agentis released from the container for the extended time. The binding agentmay comprise particles of material. The binding agent may comprise a pHsensitive binding agent. The binding agent may comprise a salt sensitivebinding agent. The binding agent may comprise a pH sensitive bindingagent configured to reversibly couple to the therapeutic agent at anon-physiologic pH below 6.5 or above 8 and to release the therapeuticagent at a physiologic pH of about 7. The pH sensitive binding agent canbe configured to reversibly couple to the therapeutic agent at a pH ofabout 5 to about 6.5 and to release the therapeutic agent at aphysiologic pH of about 7.

A stabilizer may extend release of the therapeutic agent. The stabilizermay comprise a buffer disposed within the container to decrease the pHwithin the container when the device is placed in the eye. The buffermay comprise a macromolecule having a molecular weight of at least about2 k Daltons. The stabilizer may comprise an erodible material. Theerodible material may decrease the pH when the material erodes.

In many embodiments, the container comprises a reservoir having acapacity from about 0.005 cc to about 2 cc to deliver therapeuticamounts of the therapeutic agent for the extended time and wherein thedevice comprises a volume of no more than about 0.25 cc to minimizedistension of the eye when the device is inserted.

In many embodiments, the reservoir has a capacity from about 0.005 cc toabout 0.6 cc to deliver therapeutic amounts of the therapeutic agent forthe extended time and wherein the device comprises a volume of no morethan about 0.6 cc to minimize distension of the eye when the device isinserted.

In many embodiments, the therapeutic device comprising a lengthextending through the sclera and into the vitreous humor and the lengthis within a range from about 2 to 12 mm. The length can be within arange from about 4 to 6 mm.

In many embodiments, the device further comprises a retention structurecoupled to the container and configured to couple to the sclera toretain the container at least partially within the eye. The retentionstructure may comprise an extension coupled to the container andextending outward from the container to extend between the sclera andthe conjunctiva to retain the container. The retention structure maycomprise a collar. The collar may comprise an expandable collar.

In many embodiments, the device further comprises an injection portextending to the container and having a channel extending through thesclera to receive an injection of therapeutic agent to refill thecontainer when the container is implanted at least partially within thevitreous humor. The device may further comprise a needle stop to limitpenetration of the needle when the therapeutic agent is injected intothe container. The needle stop can be disposed on a distal end of thecontainer opposite the injection port. The injection port may comprise asmooth upper surface configured for placement under the conjunctiva.

In many embodiments, the device further comprising a bactericidal agentaround at least a portion of an outer surface of the device to inhibitbacterial growth along the outer surface.

In many embodiments, the device further comprises a sponge to encouragetissue ingrowth. The sponge may comprise a bactericidal agent.Alternatively, the sponge may not comprise a bactericidal agent.

In many embodiments, the device further comprises a sponge materialimpregnated with the bactericidal agent around the portion of the outersurface. The sponge material may comprise collagen and the bactericidalagent may comprise sliver, the collagen impregnated with the silver.

In many embodiments, the container comprises a plurality of chambersconnected with a plurality of channels to linearize a rate of release ofthe therapeutic agent.

In another aspect embodiments provide therapeutic device to treat an eyecomprising a vitreous humor. The device comprises a therapeutic agentand a binding agent. The therapeutic agent is reversibly coupled to thebinding agent such that the binding agent releases therapeutic amountsof the therapeutic agent into the vitreous humor of the eye for anextended time.

In many embodiments, the binding agent and the therapeutic agent aresized for injection into a vitreous humor of the eye when thetherapeutic agent is reversibly coupled to the binding agent and whereinthe binding agent is configured to release therapeutic amounts of thetherapeutic agent for at least about 3 months. The binding agent maycomprise a size of no more than about 1000 nm to minimize light scatterand at least about 5 nm such that the therapeutic agent coupled to thebinding agent is retained in the vitreous humor for the extended time.The binding agent may comprise particles having a size of no more thanabout 100 nm to minimize light scatter and at least about 5 nm such thatthe therapeutic agent coupled to the binding agent is retained in thevitreous humor for the extended time.

In another aspect embodiments provide a therapeutic device to deliver atherapeutic agent to an eye having a sclera and a vitreous humor. Thedevice comprises a retention structure configured to couple to thesclera. A container is coupled to the retention structure and configuredto hold the therapeutic agent. The container comprises a chamber to holdthe therapeutic agent, and a barrier to inhibit flow of the therapeuticagent from the container. The barrier comprises at least one opening torelease the therapeutic agent to the vitreous humor. A porous structureis disposed between the barrier and the chamber to release thetherapeutic agent into the vitreous humor through the at least oneopening at therapeutic amounts for an extended time.

In many embodiments, the porous structure comprises a glass frit.

In many embodiments, the porous structure may comprise a porous annularportion and a porous circular end.

In many embodiments, the barrier comprises a material to inhibitsubstantially the release of the therapeutic agent from the containerand the material is shaped so as to define the at least one opening torelease the therapeutic agent.

In many embodiments, the barrier comprises a substantially non-porousmaterial to inhibit substantially the release of the therapeutic agentfrom the container.

In many embodiments, the barrier comprises a tube and the porousstructure comprises a circular disk disposed near the end of the tube.

In many embodiments, porous structure comprises a removable cartridgeconfigured for placement and removal when the barrier is positioned inthe eye and the retention structure is coupled to the sclera to retainthe barrier.

In another aspect embodiments provide a therapeutic device to deliver atherapeutic agent to an eye having a sclera and a vitreous humor. Aretention structure is configured to couple to the sclera. A containeris coupled to the retention structure and configured to hold thetherapeutic agent and a binding agent. A porous barrier is coupled tothe retention structure and the rigid container. The porous barrierextends substantially around the container.

In many embodiments, the therapeutic agent and the binding agent areconfigured to release the therapeutic agent at therapeutic amounts for asustained time.

In many embodiments, the device further comprises at least one openingformed in the container, and the opening is sized such that thetherapeutic agent and the binding agent are configured to release thetherapeutic agent through the at least one opening at therapeuticamounts for the sustained time.

In many embodiments, the porous barrier is configured to inhibit atleast one of bacterial migration into the container, macrophagemigration into the container or antibody migration into the container.

In many embodiments, the porous barrier comprises pores sized to passthe therapeutic agent from the container to the vitreous humor.

In many embodiments, the porous barrier comprises a pore size of atleast about 10 nm to release the therapeutic agent and no more thanabout 200 nm to inhibit at least one of bacterial migration out of thecontainer, macrophage migration or antibody migration into thecontainer.

In many embodiments, the porous barrier comprises a flexible material.

In many embodiments, the porous barrier comprises an inflatable balloonconfigured to inflate when the therapeutic agent is injected into thecontainer.

In many embodiments, the container comprises a rigid material to retainthe therapeutic agent and the binding agent.

In many embodiments, the container comprises a material substantiallyimpermeable to the therapeutic agent and at least one opening sized torelease the therapeutic agent.

In many embodiments, therapeutic device further comprises an injectionport sized to receive a needle.

In another aspect embodiments provide a therapeutic device to deliver atherapeutic agent to an eye having a sclera and a vitreous humor. Aretention structure is configured to couple to the sclera. A containeris coupled to the retention structure and configured to hold atherapeutic quantity of the therapeutic agent. The container comprises afirst chamber to hold the therapeutic agent, and a barrier to inhibitflow of the therapeutic agent from the container. The barrier comprisesat least one opening sized to release the therapeutic agent. A secondchamber is coupled to the container through the at least one opening.The second chamber is configured to couple to the vitreous humor througha second at least one opening. The first at least one opening and thesecond at least one opening are sized to release the therapeutic agentinto the vitreous humor through the second at least one opening attherapeutic amounts for an extended time.

In many embodiments, the second chamber comprises a volume sized tolinearize a release rate of the therapeutic agent through the second atleast one opening.

In another aspect, embodiments provide a method of sustained drugdelivery to a posterior segment of an eye having a sclera and a vitreoushumor. A container is inserted at least partially into the vitreoushumor of the eye such that the container is retained with the sclera.The container comprises a first portion of therapeutic agent reversiblycoupled to a first binding medium. The first portion of therapeuticagent is released from the first binding medium and through container tothe vitreous at therapeutic amounts for an extended time. The bindingmedium is removed from the container. The binding medium is replacedwith a second binding medium and a second portion of the therapeuticagent, wherein second portion of the therapeutic agent is released fromthe container for a second extended time.

In many embodiments, a protective barrier is inserted with the containerand the protective barrier is disposed substantially around thecontainer to inhibit at least one of a bacterial migration, a macrophagemigration or an antibody migration into the container.

In many embodiments, first binding medium comprises at least one of afirst insert, a first fibrous structure, a first slurry, or a firstliquid and wherein the second binding medium comprises at least one of asecond insert, a second fibrous structure, a second slurry or a secondliquid.

In many embodiments, the liquid first binding medium is removed when thesecond binding medium is replaced.

In many embodiments, the first binding medium is removed when the secondliquid is replaced to minimize volume changes within the eye.

In many embodiments, the first binding medium is removed when the secondliquid is replaced to decrease volume changes within the eye.

In many embodiments, the first binding medium is removed when the secondliquid is replaced to inhibit distension of the eye.

In many embodiments, the binding medium comprises an insert and whereinthe insert is removed before a second insert is inserted.

In another aspect, embodiments provide a device to deliver a therapeuticagent to a container implanted at least partially in the eye. The devicecomprises a first chamber configured to store the therapeutic agent, anda second chamber configured to receive a liquid from the container. Anelongate structure extends distally and comprising at least one channelcoupled to the first chamber and the second chamber.

In many embodiments, the device further comprises a first one way valvecoupled to the first chamber and the at least one channel. The first oneway valve is configured to pass the therapeutic agent when a size of thefirst chamber decreases and inhibit flow into the first chamber from thechannel when the size of the first chamber increases. A second one wayvalve can be coupled to the second chamber and the at least one channel.The second one way valve can be configured to inhibit flow of thetherapeutic agent into the second chamber when a size of the firstchamber decreases and to permit flow into the second chamber from thechannel when the size of the first chamber increases.

In many embodiments, the first at least one channel comprises a firstchannel and a second channel. The first channel is coupled to the firstchamber to inject the therapeutic agent and the second channel iscoupled to the second chamber to draw fluid into the second chamber whenthe therapeutic agent is injected.

In another aspect embodiments provide therapeutic device to deliver atherapeutic agent to an eye having a sclera and a vitreous humor. Aretention structure is configured to couple to the sclera. A containeris coupled to the retention structure and configured to hold thetherapeutic agent. A stop is disposed inside the container.

In many embodiments, the retention structure is configured to receive aneedle.

In many embodiments, the stop comprises a concave surface directedtoward the retention structure such that fluid is mixed within thecontainer when a substance is injected with the needle.

In many embodiments, the container comprises at least one exit port topass material from the container when the substance is injected with theneedle, and the at least one exit is located distal to the concavesurface such that the concave surface directs the injected substanceaway from the at least one exit port.

In another aspect embodiments provide a therapeutic device to release atleast one therapeutic agent into a patient. The therapeutic devicecomprises a container to contain a therapeutic amount of the at leastone therapeutic agent. The container comprises a reservoir with a volumesized to contain a therapeutic quantity of the at least one therapeuticagent for release over the extended time. The container comprises arigid porous structure comprising a thickness and a surface area coupledto the reservoir and configured to release therapeutic amounts of the atleast one therapeutic agent for the extended time.

In many embodiments, the container comprises a penetrable barrierconfigured to receive an injection of a therapeutic quantity of the atleast one therapeutic agent, and the container comprises a barriercoupled to the penetrable barrier and the rigid porous structure tocontain the at least one therapeutic agent.

In many embodiments, the barrier is coupled to the penetrable barriercomprises a tube.

In many embodiments, the rigid porous structure comprises a needle stop.

In many embodiments, the penetrable barrier comprises a septumconfigured to receive and pass a needle, and the septum is configured toseal when the needle is removed.

In many embodiments, the channels of the rigid porous structurecomprises interconnected substantially fixed channels. The rigid porousstructure can remain rigid and the channels can remain substantiallyfixed when the therapeutic agent is injected into the reservoir with atleast some pressure.

In many embodiments, the rigid porous structure comprises a thicknesswithin a range from about 0.1 mm to about 6 mm.

In many embodiments, the rigid porous structure comprises a thicknesswithin a range from about 0.5 mm to about 6 mm.

In many embodiments, the rigid porous structure comprises a hardnessparameter within a range from about 160 Vickers to about 500 Vickers.The rigid porous structure may comprise a hardness parameter within arange from about 200 Vickers to about 240 Vickers.

In many embodiments, the rigid porous structure comprises a surface areawithin a range from about 2 mm(^2) to 0.2 mm(^2).

In many embodiments, the rigid porous structure comprises a lowresistance to flow. The porous structure may comprise a porosity tomaintain the low resistance to flow. The porous structure may comprise aplurality of interconnecting channels extending between openings of afirst side of the porous structure and openings of a second side of theporous structure to maintain the low resistance to flow.Inter-connections among the plurality of interconnecting channels canmaintain the low resistance to flow when at least some of the channelsare blocked.

In many embodiments, the low resistance to flow corresponds to aresistance no more than a resistance of a needle sized to inject thetherapeutic agent into the reservoir.

In many embodiments, the low resistance to flow corresponds to apressure drop across the porous structure of no more than about 30 mm Hgwhen the therapeutic agent is injected. The pressure drop across theporous structure may comprise no more than about 20 mm Hg when thetherapeutic agent is injected such that a physician can determine thepresence of blockage of the interconnecting channels when thetherapeutic agent is injected.

In many embodiments, the pressure drop across the porous structurecorresponds to no more than a pressure drop of 35 Gauge needle to injectthe therapeutic agent.

In many embodiments, the pressure drop across the porous structurecorresponds to no more than a pressure drop of 35 Gauge needle having alength sized to inject the therapeutic agent into the reservoir.

In many embodiments, the rigid porous structure comprises a resistanceto flow of an injected solution or suspension through a thirty gaugeneedle such that ejection of said solution or suspension through therigid porous structure is substantially inhibited when said solution orsuspension is injected into the reservoir. The reservoir may comprise avent.

In many embodiments, the volume of the reservoir comprises from about 5uL to about 2000 uL of a solution or suspension of the at least onetherapeutic agent to release the at least one therapeutic agent for theextended period.

In many embodiments, the volume of the reservoir comprises from about 10uL to about 200 uL of a solution or suspension of the at least onetherapeutic agent to release the at least one therapeutic agent for theextended period.

In many embodiments, therapeutic device further comprises a retentionstructure affixed to the container and configured to couple to at leastone tissue structure of the patient for the extended period. The atleast one tissue structure may comprise a sclera of an eye of thepatient and wherein the rigid porous structure is disposed on at least aportion of the container to release the at least one therapeutic agentinto the eye for the extended period. The rigid porous structure can bedisposed on at least a portion of the container to release the at leastone therapeutic agent into at least one of the vitreous humor, theaqueous humor, the choroid, the sclera or the retina of the eye for theextended period.

In many embodiments, the rigid porous structure is disposed on a distalportion of the container to release the at least one therapeutic agentinto the vitreous humor for convective transport to the retina of theeye for the extended period.

In many embodiments, the rigid porous structure is disposed on aproximal portion of the container to release the at least onetherapeutic agent into the vitreous humor to couple to one or more of aciliary body or a trabecular meshwork of the eye.

In many embodiments, the rigid porous structure comprises a surfaceoriented toward a target tissue of the eye when positioned in the eye.

In many embodiments, the rigid porous structure comprises a surfaceoriented away from a lens of the eye and toward a retina of the eye whenpositioned in the eye.

In many embodiments, the rigid porous structure comprises a surfaceoriented away from a lens of the eye and toward a retina of the eye toinhibit a cataract when positioned in the eye.

In many embodiments, the at least one tissue structure comprises aconjunctiva of the eye and the retention structure is configured toextend outward from the container between the sclera and the conjunctivato retain the container for the extended period. The container maycomprise a penetrable barrier and wherein the penetrable barrier and theretention structure are each configured to minimize erosion ofsurrounding tissues when positioned in an eye. The retention structurecan inhibit or prevent the device from moving into the eye duringrefilling.

The retention structure may extend outward from the container andcomprise at least one of a suture hole for attachment to the sclera viaa standard suture.

In many embodiments, the rigid porous structure comprises a plurality ofrigid porous structures coupled to the reservoir and configured torelease the at least one therapeutic agent for the extended period.

In many embodiments, the rigid porous structure comprises a molded rigidporous structure. The molded rigid porous structure may comprise atleast one of a disk, a helix or a tube coupled to the reservoir andconfigured to release the at least one therapeutic agent for theextended period.

In many embodiments, the reservoir and the porous structure areconfigured to release therapeutic amounts of the at least onetherapeutic agent corresponding to a concentration of at least about0.001 μg per ml of vitreous humor for an extended period of at leastabout three months.

In many embodiments, the reservoir and the porous structure areconfigured to release therapeutic amounts of the at least onetherapeutic agent corresponding to a concentration of at least about0.01 μg per ml of vitreous humor and no more than about 300 μg per mlfor an extended period of at least about three months. The reservoir andthe porous structure can be configured to release therapeutic amounts ofthe at least one therapeutic agent corresponding to a concentration ofat least about 0.1 μg per ml of vitreous humor. The reservoir and theporous structure can be configured to release no more than about 10 μgper ml for the extended period of at least about three months.

In many embodiments, the at least one therapeutic agent comprises aprotein or peptide and a molecular weight of at least about 10k Daltons.

In many embodiments, the at least one therapeutic agent comprises a VEGFinhibitor.

In many embodiments, the at least one therapeutic agent comprises atleast a fragment of an antibody and a molecular weight of at least about10k Daltons. The at least one therapeutic agent may compriseranibizumab. The at least one therapeutic agent may comprisebevacizumab. The at least one therapeutic agent may compriseAflibercept™.

In many embodiments, the reservoir and the porous structure areconfigured to release therapeutic amounts of the at least onetherapeutic agent corresponding to a concentration of at least about 0.1ug per ml of vitreous humor. The reservoir and the porous structure canbe configured to release no more than about 10 ug per ml for an extendedperiod of at least about 6 months.

In many embodiments, the reservoir and the porous structure areconfigured to release therapeutic amounts of the at least onetherapeutic agent corresponding to a concentration of at least about 0.1ug per ml of vitreous humor and no more than about 10 ug per ml for anextended period of at least about twelve months. The reservoir and theporous structure can be configured to release therapeutic amounts of theat least one therapeutic agent corresponding to a concentration of atleast about 0.1 ug per ml of vitreous humor and no more than about 10 ugper ml for an extended period of at least about twelve months.

In many embodiments, the interconnecting channels of the rigid porousstructure are sized to limit a size of molecules passed through thechannels of the rigid porous structure.

In many embodiments, the channels of the rigid porous structure comprisea hydrogel configured to limit a size of molecules passed through thechannels of the rigid porous structure. The hydrogel can be configuredto pass the at least one therapeutic agent comprising moleculescomprising a cross-sectional size of no more than about 10 nm. Thehydrogel may comprise a water content of at least about 70%. Thehydrogel may comprise a water content of no more than about 90% to limitmolecular weight of the at least one therapeutic agent to about 30kDaltons. The hydrogel may comprise a water content of no more than about95% to limit molecular weight of the at least one therapeutic agent toabout 100k Daltons. The hydrogel may comprise a water content within arange from about 90% to about 95% such that the channels of the porousmaterial are configured to pass Ranibizumab and substantially not passBevacizumab.

In many embodiments, the Ranibizumab comprises ranibizumab comprising arecombinant humanized IgG1 kappa monoclonal antibody Fab fragmentdesigned for intraocular use and wherein the ranibizumab is configuredto bind to and inhibit the biologic activity of human vascularendothelial growth factor A (VEGF-A) and wherein the Ranibizumab has amolecular weight of approximately 48 k Daltons.

In many embodiments, the bevacizumab comprises a recombinant humanizedmonoclonal IgG1 antibody configured to bind to and inhibits the biologicactivity of human vascular endothelial growth factor (VEGF) and whereinbevacizumab comprises human framework regions and thecomplementarity-determining regions of a murine antibody configured tobind to VEGF and wherein the bevacizumab has a molecular weight ofapproximately 149 k Daltons.

In many embodiments, the porous structure comprises a porosity, athickness, a channel parameter and a surface area configured to releasetherapeutic amounts for the extended period. The porosity may comprise avalue within a range from about 3% to about 70%. The porosity maycomprise a value within a range from about 3% to about 30%. The porositymay comprise a value within a range from about 5% to about 10%. Theporosity may comprise a value within a range is from about 10% to about25%. The porosity may comprise a value within a range is from about 10%to about 20%.

In many embodiments, the channel parameter comprises a fit parametercorresponding to the tortuosity of the channels.

In many embodiments, the channel parameter comprises a fit parametercorresponding to an effective length of interconnecting channelsextending from a first side of the porous structure to a second side ofthe porous structure. The effective length of the interconnectingchannels may correspond to at least about 2 times a thickness of theporous structure. The effective length of the interconnecting channelsmay correspond to at least about 5 times a thickness of the porousstructure.

In many embodiments, the rate of release of the at least one therapeuticagent corresponds to a ratio of the porosity to the channel parameter,and the ratio of the porosity to the channel parameter is less thanabout 0.5 such that the porous structure releases the at least onetherapeutic agent for the extended period. The ratio of the porosity tothe channel parameter can be less than about 0.2 such that the porousstructure releases the at least one therapeutic agent for the extendedperiod. The ratio of the porosity to the channel parameter can be lessthan about 0.1 such that the porous structure releases the at least onetherapeutic agent for the extended period. The ratio of the porosity tothe channel parameter can be less than about 0.05 such that the porousstructure releases the at least one therapeutic agent for the extendedperiod.

In many embodiments, the channel parameter comprises a value of at leastabout 1. The value of the channel parameter may comprise at least about2. The channel parameter may comprise a value of at least about 5.

In many embodiments, porous structure comprises a release rate indexdetermined with a ratio of the porosity times a cross-sectional area ofthe porous structure divided by the channel parameter times a thicknessof the porous structure, the thickness extending across the crosssectional area. The porous structure may comprise a release rate indexof no more than about 5.0 mm. The porous structure may comprise arelease rate index of no more than about 2 mm. The porous structure maycomprise a release rate index of no more than about 1.2 mm. The porousstructure may comprise a release rate index of no more than about 0.2mm. The porous structure may comprise a release rate index of no morethan about 0.1 mm. The porous structure may comprise a release rateindex of no more than about 0.05 mm.

In many embodiments, the channels of the rigid porous structure aresized to pass the at least one therapeutic agent comprising moleculeshaving a molecular weight of at least about 100 Daltons.

In many embodiments, the channels of the rigid porous structure aresized to pass the at least one therapeutic agent comprising moleculeshaving a molecular weight of at least about 50k Daltons.

In many embodiments, the channels of the rigid porous structurecomprises interconnecting channels configured to pass the at least onetherapeutic agent among the interconnecting channels. The rigid porousstructure may comprise grains of rigid material and wherein theinterconnecting channels extend at least partially around the grains ofrigid material to pass the at least one therapeutic agent through theporous material. The grains of rigid material can be coupled together atloci of attachment, and the interconnecting channels can extend at leastpartially around the loci of attachment.

In many embodiments, the porous structure comprises a sintered material.The sintered material may comprise grains of material in which thegrains comprise an average size of no more than about 20 um. Thesintered material may comprise grains of material in which the grainscomprise an average size of no more than about 10 um. The sinteredmaterial may comprise grains of material in which the grains comprise anaverage size of no more than about 5 um. The sintered material maycomprise grains of material in which the grains comprise an average sizeof no more than about 1 um.

In many embodiments, the sintered material comprises grains of materialcorresponding to a media grade of no more than about 0.1. The sinteredmaterial comprises grains of material corresponding to a media grade ofno more than about 0.2. The sintered material may comprise grains ofmaterial corresponding to a media grade of no more than about 0.3. Thesintered material may comprise grains of material corresponding to amedia grade of no more than about 0.5.

In many embodiments, the channels are sized to pass therapeuticquantities of the at least one therapeutic agent through the sinteredmaterial for the extended time.

In many embodiments, the channels are sized to inhibit penetration ofmicrobes through the sintered material. The channels are sized toinhibit penetration of bacteria through the sintered material.

In many embodiments, the sintered material comprises a wettablematerial. The sintered material may comprise a wettable material toinhibit bubbles within the channels of the material.

In many embodiments, the sintered material comprises at least one of ametal, a ceramic, a glass or a plastic. The sintered material maycomprises a sintered composite material and the composite material maycomprises two or more of the metal, the ceramic, the glass or theplastic. The sintered material may comprise the metal and the metal maycomprise at least one of Ni, Ti, nitinol, stainless steel, cobaltchrome, elgiloy, hastealloy, c-276 alloy or Nickel 200 alloy. Thesintered material may comprise the metal and the metal may comprise atleast one of stainless steel 304, 304L, 316 or 316L. The sinteredmaterial comprises a ceramic. The sintered material comprises the glass.The sintered material comprises the plastic, the plastic comprising awettable coating to inhibit bubble formation in the channels and whereinthe plastic comprises at least one of PEEK, polyethylene, polypropylene,polyimide, polystyrene, polyacrylate, polymethacrylate, or polyamide.

In many embodiments, the at least one therapeutic agent stored in thereservoir of the container comprises at least one of a solid comprisingthe at least one therapeutic agent, a solution comprising the at leastone therapeutic agent, a suspension comprising the at least onetherapeutic agent, particles comprising the at least one therapeuticagent adsorbed thereon, or particles reversibly bound to the at leastone therapeutic agent.

In many embodiments, the device is sized to pass through a lumen of acannula.

In another aspect embodiments provide therapeutic device to release atleast one therapeutic agent into a patient having a retina. Thetherapeutic device comprises a container to contain a therapeutic amountof the at least one therapeutic agent. The container comprises areservoir with a volume sized to contain a therapeutic quantity of theat least one therapeutic agent for release over the extended time. Thecontainer comprises a porous structure comprising a thickness and asurface area coupled to the reservoir and configured to releasetherapeutic amounts of the at least one therapeutic agent for theextended time. The porous structure is disposed on a distal portion ofthe container. A retention structure is coupled to the container tocouple to a sclera of the eye and position the porous structure at alocation of the eye to deliver the therapeutic agent toward a targetregion of the retina with convective flow of the vitreous humor.

In many embodiments, the target location of the retina corresponds toneovascularization of a lesion coupled to the target region of theretina.

In many embodiments, the therapeutic agent comprises a macromolecule andwherein the porous structure comprises interconnecting channels sized topass the macromolecule.

In many embodiments, the therapeutic agent comprises a steroid andwherein the porous structure comprises a surface oriented away from alens of the eye to inhibit formation of a cataract when the steroid isreleased.

In another aspect embodiments provide therapeutic device to release atleast one therapeutic agent into a patient having a retina. Thetherapeutic device comprises a container to contain a therapeutic amountof the at least one therapeutic agent. The container comprises areservoir with a volume sized to contain a therapeutic quantity of theat least one therapeutic agent for release over the extended time. Thecontainer comprises a porous structure comprising a thickness and asurface area coupled to the reservoir and configured to releasetherapeutic amounts of the at least one therapeutic agent for theextended time. The porous structure is disposed on a proximal portion ofthe container. A retention structure is coupled to the container tocouple to a sclera of the eye and position the porous structure at alocation of the eye to deliver the therapeutic agent to one or more ofthe ciliary body or a trabecular meshwork of the eye to treat glaucoma.

In many embodiments, the therapeutic agent comprises a prostaglandin ora prostaglandin analog.

In another aspect embodiments provide a method of treating an eye of ahaving a vitreous humor and a retina. A target location of the retina isidentified for treatment. A container is positioned, and the containerhas a therapeutic amount of a therapeutic agent. The container comprisesa porous structure to release therapeutic amounts of the at least onetherapeutic agent for the extended time. The porous structure ispositioned in the vitreous humor at a location away from the retina todeliver the therapeutic agent to the target location with convectiveflow of the vitreous humor.

In many embodiments, the target location comprises choroidalneovascularization of a choroid of the eye coupled to the targetlocation of the retina and wherein the therapeutic agent comprises amacromolecule to treat the choroidal neovascularization.

In many embodiments, the therapeutic agent comprises a macromolecule andwherein the container is coupled to the sclera and sized to position theporous structure along a flow path of the vitreous humor extendingtoward the target location.

In another aspect embodiments provide a therapeutic device to release atleast one therapeutic agent into an eye of a patient. The therapeuticdevice comprises a container to contain a therapeutic amount of the atleast one therapeutic agent. The container comprises a reservoir with avolume sized to contain a therapeutic quantity of the at least onetherapeutic agent for release over the extended time. The containercomprises a rigid porous structure comprising a thickness, a surfacearea and interconnecting channels coupled to the reservoir andconfigured to release therapeutic amounts of the at least onetherapeutic agent for the extended time, the rigid porous structuredisposed on a distal portion of the container to release the at leastone therapeutic agent into the eye. A penetrable barrier is coupled tothe reservoir and disposed on a proximal portion of the container toreceive an injection of the at least one therapeutic agent. A retentionstructure is affixed to the container and configured to couple to atissue of the eye of the patient for the extended period.

In another aspect embodiments provide a method of treating an eye. Acontainer comprising a reservoir and a penetrable barrier is placed atleast partially through a sclera of the eye, wherein the reservoircomprises a fluid. At least one needle is passed through the penetrablebarrier and the conjunctiva disposed over the penetrable barrier. Atherapeutic amount of at least one therapeutic agent is injected intothe container. The fluid in the reservoir is substantially removed fromthe container when the therapeutic amount is injected.

In many embodiments, the fluid comprises a buffer.

In many embodiments, the fluid comprises at least one therapeutic agent.

In many embodiments, the at least one needle penetrates the penetrablebarrier at a locus of penetration, the method further comprisingremoving the at least one needle from the penetrable barrier.

In many embodiments, the container comprises a rigid porous sinteredmaterial configured to release the at least one therapeutic agent fromthe container for an extended period of at least about three months, andthe rigid porous sintered material comprises a needle stop disposedopposite the penetrable barrier.

In many embodiments, the at least one therapeutic agent is removed fromthe container with an injection of a solution in response to a patientreaction to the at least one therapeutic agent. An additional amount ofthe at least one therapeutic agent may be injected into the container toresume treatment of the patient with the at least one therapeutic agent.

In many embodiments, the at least one therapeutic agent injected intothe container comprises at least one of a suspension of solid particlesof the at least one therapeutic agent, a solution of the at least onetherapeutic agent, at least one therapeutic agent adsorbed on particlesor at least one therapeutic agent reversibly bound on particles.

In another aspect, embodiments provide a device to inject at least onetherapeutic agent into a container positioned at least partially withinthe eye. The device comprises a chamber to hold a therapeutic quantityof at least one therapeutic agent. At least one needle is coupled to thechamber and comprising a first lumen sized to inject the at least onetherapeutic agent into the container and a second lumen sized to receiveliquid from the container when a quantity of at least one therapeuticagent is injected.

In many embodiments, the at least one needle comprises a first needlecoupled to the chamber and a second needle coupled to a receptacle toreceive the liquid ejected from the container when the at least onetherapeutic agent is injected.

In many embodiments, the at least one needle comprises a first needlecoupled to the chamber and a second needle coupled to a receptacle undervacuum to receive the liquid ejected from the container when the atleast one therapeutic agent is injected.

In many embodiments, the first lumen extends to a first opening and thesecond lumen extends to a second opening, the first opening spaced apartfrom the second opening such that the liquid of the container issubstantially replaced when the quantity of the at least one therapeuticagent is injected.

In another aspect, embodiments provide a therapeutic device to releaseat least one therapeutic agent into a vitreous humor of an eye of apatient. The therapeutic device comprises a container to contain atherapeutic amount of the at least one therapeutic agent, the containercomprising a reservoir with a volume sized to contain a therapeuticquantity of at least one therapeutic agent for release over an extendedtime of at least one year. The reservoir comprises a volume of at leastabout 10 uL. The container comprises a barrier coupled to the reservoirand disposed along at least a portion of the reservoir container tocontain therapeutic agent within the reservoir. A porous structurecomprising a thickness, a surface area and channels is coupled to thereservoir and configured to release therapeutic amounts of the at leastone therapeutic agent for the extended time of at least one year, theporous structure is coupled to the container to release the at least onetherapeutic agent into the eye. A retention structure is affixed to thecontainer and configured to couple to a sclera of the eye of the patientfor the extended period.

In many embodiments, the at least one therapeutic agent comprisesranibizumab.

In many embodiments, the at least one therapeutic agent comprisesbevacizumab.

In many embodiments, the at least one therapeutic agent comprisessteroids, nonsteroidals, anti-inflammatories, antibiotics, glaucomatreatments or neuroprotectives.

In many embodiments, the quantity comprises at least about 20 uL andwherein the extended time comprises at least about two years and amolecular weight of the at least one therapeutic agent comprises atleast about 100 Daltons.

In many embodiments, the quantity comprises at least about 20 uL andwherein the extended time comprises at least about two years and amolecular weight of the at least one therapeutic agent comprises atleast about 10 k Daltons.

In many embodiments, the quantity comprises at least about 30 uL andwherein the extended time comprises at least about three years and amolecular weight of the at least one therapeutic agent comprises atleast about 100 Daltons.

In many embodiments, the quantity comprises at least about 30 uL andwherein the extended time comprises at least about three years and amolecular weight of the at least one therapeutic agent comprises atleast about 10 k Daltons.

In another aspect, embodiments provide a therapeutic device to releaseat least one therapeutic agent into a vitreous humor of an eye of apatient. The therapeutic device comprises a container to contain atherapeutic amount of the at least one therapeutic agent. The containercomprises a reservoir with a volume sized to contain a therapeuticquantity of at least one therapeutic agent for release over an extendedtime. The container comprises a barrier coupled to the reservoir anddisposed along at least a portion of the reservoir container to containtherapeutic agent within the reservoir. A porous structure comprising afirst side having comprising a first plurality of openings is coupled tothe reservoir and a second side comprises a second plurality of openingsto couple to the vitreous humor. The interconnecting channels extendbetween each of the first plurality of openings of the first side andeach of the second plurality of openings of the second side to maintainrelease of the therapeutic agent through the porous structure whenpartially blocked. A retention structure is affixed to the container tocouple to a sclera of the eye of the patient for the extended period.

In many embodiments, the release of the therapeutic agent through theporous structure is maintained when partially blocked with particles.

In many embodiments, the release of the therapeutic agent through theporous structure is maintained when partially blocked with particles.

In many embodiments, the release of the therapeutic agent through theporous structure is maintained when partially blocked with particlescomprising one or more of degraded therapeutic agent or aggregatedtherapeutic agent. The particles may comprise the degraded therapeuticagent, and the degraded therapeutic agent may comprise a conformationalchange of a molecular structure of the therapeutic agent such thatefficacy of the degraded therapeutic agent is less than the therapeuticagent. The particles may comprise the degraded therapeutic agent and thedegraded therapeutic agent may comprise at least one altered chemicalbond such that the molecules of the therapeutic agent such that efficacyof the degraded therapeutic agent is less than the therapeutic agent.The particles may comprise the aggregated therapeutic agent and whereinthe aggregated therapeutic agent comprises a plurality of molecules ofthe therapeutic agent.

In many embodiments, the release of the therapeutic agent through theporous structure is maintained when a portion of the first side or thesecond side is blocked with a covering material.

In another aspect, embodiments provide a therapeutic device to releaseat least one therapeutic agent into a vitreous humor of an eye of apatient. The therapeutic device comprises a container to contain atherapeutic amount of the at least one therapeutic agent, the containercomprising a reservoir with a volume sized to contain a therapeuticquantity of at least one therapeutic agent for release over an extendedtime. The container comprises a barrier coupled to the reservoir anddisposed along at least a portion of the reservoir container to containtherapeutic agent within the reservoir. A porous structure comprises afirst side having comprising a first area coupled to the reservoir and asecond side having a second area to couple to the vitreous humor. A flowrate of the therapeutic agent through the porous structure decreasesless than a per cent amount when the first area or the second area aredecreased by the per cent amount. A retention structure is affixed tothe container to couple to a sclera of the eye of the patient for theextended period.

In many embodiments, the flow rate of the therapeutic agent through theporous structure decreases less than the per cent amount when the firstarea and the second area are decreased by the per cent amount.

In many embodiments, a flow rate of the therapeutic agent through theporous structure decreases less than five per cent amount when the firstarea or the second area are decreased by the five percent.

In another aspect, embodiments provide a therapeutic device to releaseat least one therapeutic agent into a vitreous humor of an eye of apatient. The therapeutic device comprises a container to contain atherapeutic amount of the at least one therapeutic agent. The containercomprises a reservoir with a volume sized to contain a therapeuticquantity of at least one therapeutic agent for release over an extendedtime. The container comprises a barrier coupled to the reservoir anddisposed along at least a portion of the reservoir container to containtherapeutic agent within the reservoir. A porous structure comprises afirst side having a first plurality of openings coupled to the reservoirand a second side having a second plurality of openings to couple to thevitreous humor. Interconnecting channels extend from the first pluralityof openings on the first side to the second plurality of openings on thesecond side to connect each of the plurality of openings on the firstside with each of the plurality of openings on the second side. Aretention structure is affixed to the container and configured to coupleto a sclera of the eye of the patient for the extended period.

In many embodiments, the first plurality comprises at least about 10openings on the first side and the second plurality comprises at leastabout 10 openings on the second side and each of the at least about 10openings of the first side is connected to each of the at least about 10openings on the second side with the interconnecting channels.

In many embodiments, the first plurality comprises at least about 20openings on the first side and the second plurality comprises at leastabout 20 openings on the second side and each of the at least about 20openings of the first side is connected to each of the at least about 20openings on the second side with the interconnecting channels.

In many embodiments, the first plurality comprises at least about 40openings on the first side and the second plurality comprises at leastabout 40 openings on the second side and each of the at least about 40openings of the first side is connected to each of the at least about 40openings on the second side with the interconnecting channels.

In another aspect, embodiments provide a therapeutic device to releaseat least one therapeutic agent into a vitreous humor of an eye of apatient. The therapeutic device comprises a container to contain atherapeutic amount of the at least one therapeutic agent. The containercomprises a reservoir with a volume sized to contain a therapeuticquantity of at least one therapeutic agent for release over an extendedtime. The container comprises a barrier coupled to the reservoir anddisposed along at least a portion of the reservoir container to containtherapeutic agent within the reservoir. A porous structure comprises afirst side having a first plurality of openings coupled to the reservoirand a second side comprising a second plurality of openings to couple tothe vitreous humor. The porous material comprises particles sintered toform interconnecting channels extending between each of the firstplurality of openings of the first side and each of the second pluralityof openings of the second side. Release of the therapeutic agent throughthe porous structure corresponds substantially to a distribution ofsizes of the sintered material and a porosity of the sintered materialabove a percolation threshold. A retention structure is affixed to thecontainer to couple to a sclera of the eye of the patient for theextended period.

In many embodiments, the distribution corresponds to at least about tensintered particles disposed between the first plurality of openings andthe second plurality of openings to maintain release of the therapeuticagent when one or more of the first openings or the second openings ispartially blocked.

In another aspect, embodiments provide a therapeutic device to releaseat least one therapeutic agent into a vitreous humor of an eye of apatient. The therapeutic device comprises a container to contain atherapeutic amount of the at least one therapeutic agent. The containercomprises a reservoir with a volume sized to contain a therapeuticquantity of at least one therapeutic agent for release over an extendedtime. The volume corresponds to a cross-sectional dimension of thecontainer and a height of the container. The container comprises abarrier coupled to the reservoir and disposed along at least a portionof the reservoir to contain therapeutic agent within the reservoir. Aporous structure comprises a first side coupled to the reservoir and asecond side to couple to the vitreous humor. The porous structurecomprises a thickness extending between the first side and the secondside and a cross-sectional dimension corresponding to an area of thefirst side and an area of the second side. The cross-sectional dimensionof the porous structure comprises at least about ten percent of thecross-sectional dimension of the container to release the therapeuticagent for the extended time. A retention structure is affixed to thecontainer to couple to a sclera of the eye of the patient for theextended time.

In many embodiments, the cross-sectional dimension of the porousstructure comprises at least about twenty percent of the cross-sectionaldimension of the container to release the therapeutic agent for theextended time.

In many embodiments, the cross-sectional dimension of the porousstructure comprises at least about thirty percent of the cross-sectionaldimension of the container to release the therapeutic agent for theextended time.

In another aspect, embodiments provide a therapeutic device to releaseat least one therapeutic agent into a vitreous humor of an eye of apatient. The therapeutic device comprises an expandable container tocontain a therapeutic amount of the at least one therapeutic agent. Theexpandable container comprises a first narrow profile configuration forinsertion into the eye and a second expanded profile configurationhaving a reservoir sized to contain a therapeutic amount of the at leastone therapeutic agent. The expandable container comprises a porousstructure coupled to the reservoir to release the at least onetherapeutic agent. An expandable retention structure comprises a firstnarrow profile configuration for insertion at least partially into asclera of the eye and a second expanded profile configuration to coupleto the sclera of the eye. The expandable retention structure is affixedto the expandable container to couple the expandable container to thevitreous humor for the extended time.

In many embodiments, the expandable retention structure comprises aresilient material comprising one or more of metal, thermoplastic, shapememory material or Nitinol.

In many embodiments, the expandable retention structure comprises afirst extension to couple to a lower side of the sclera and a secondextension to couple to an upper side of the sclera.

In many embodiments, the first extension comprises a flange extendingdistally in the first configuration to pass through the sclera andwherein the flange extends laterally in the second configuration tocouple to the sclera.

In many embodiments, the second extension comprises a flange extendingproximally in the first configuration to pass through a lumen of aninsertion tool and wherein the flange extends laterally in the secondconfiguration to couple to the sclera.

In another aspect, embodiments provide a therapeutic device to releaseat least one therapeutic agent into a vitreous humor of an eye of apatient. The therapeutic device comprises an expandable containercomprising a first narrow profile configuration for insertion into theeye and a second expanded configuration comprising a reservoir tocontain a therapeutic amount of the at least one therapeutic agent. Theexpandable container comprises a rigid porous structure to release theat least one therapeutic agent and an expandable barrier to inhibitrelease of the at least one therapeutic agent. An expandable support isaffixed to the porous structure and the expandable barrier to couple theporous structure to the reservoir when the container has the expandedconfiguration. An expandable retention structure comprises a firstnarrow profile configuration for insertion at least partially into asclera of the eye and a second expanded profile configuration to coupleto the sclera of the eye. The expandable retention structure is affixedto the expandable container to couple the expandable container to thevitreous humor for the extended time.

In many embodiments, the expandable support comprises a resilientmaterial comprising one or more of metal, thermoplastic, shape memorymaterial or Nitinol.

In many embodiments, the expandable support comprises a proximal annularportion and a distal annular portion, wherein a plurality of membersextend between the proximal annular portion and the distal annularportion.

In many embodiments, the plurality of expandable members separatebetween the proximal annular portion and the distal annular portion whenthe container comprises the expanded configuration.

In many embodiments, the therapeutic device further comprises apenetrable barrier supported with the proximal annular portion.

In many embodiments, the rigid porous structure is supported with thedistal annular portion.

In another aspect, embodiments provide a therapeutic device to releaseat least one therapeutic agent into a vitreous humor of an eye of apatient. The therapeutic device comprises a container to contain atherapeutic amount of the at least one therapeutic agent. The containercomprises a reservoir with a volume sized to contain a therapeuticquantity of at least one therapeutic agent for release over an extendedtime. A retention structure is affixed to the container to couple to asclera of the eye of the patient for the extended time. The retentionstructure comprises an extension to couple to an upper side of thesclera. The retention structure comprises a portion to receive thesclera under the extension. The portion comprises a first widthextending in a first direction and a second width extending in a seconddirection. The first width is greater than the second width.

In many embodiments, the portion comprises an elongate cross-sectionalprofile having the first width extending along a first axis and thesecond width extending along a second axis.

In many embodiments, the portion comprises an elliptical cross-sectionalprofile having the first width extending along a first axis of theelliptical profile and the second width extending along a second axis ofthe elliptical profile.

In many embodiments, portion comprises a narrow portion having the firstwidth sized larger than a cross-sectional dimension of the container andhaving the second width sized smaller than a cross-sectional dimensionof the container to seal an incision of the sclera with thecross-sectional profile.

In many embodiments, the narrow portion comprises a recess extendingsubstantially around the narrow portion and wherein the recess comprisesa thickness sized to receive the sclera.

In many embodiments, the extension comprises a first extension widthextending in the first direction and a second extension width extendingin the second direction, the first extension width greater than thesecond extension width.

In many embodiments, the extension comprises an elliptical profilehaving the first extension width extending along a first axis of theelliptical profile and the second extension width extending along asecond axis of the elliptical profile.

In many embodiments, the container comprises a cross-sectional profilehaving a first distance across and a second distance across greater thanthe first distance across.

In many embodiments, the container comprises a cross-sectional profilehaving a first distance across and a second distance across greater thanthe first distance across and wherein the first distance is alignedsubstantially with the first width and the second dimension across isaligned substantially with the second width to decrease visualinterference.

In many embodiments, the cross-sectional profile of the containercomprises an elliptical profile.

In another aspect, embodiments provide a method of treating an eyehaving a vitreous humor and a sclera. A therapeutic device is providedto release at least one therapeutic agent into the vitreous humor of aneye of a patient. The therapeutic device comprises a container and aretention structure affixed to the container. The retention structurecomprises a narrow portion having a first longer distance acrossextending in a first direction and a second shorter distance acrossextending in a second direction. The first longer distance is greaterthan the second shorter distance. An elongate incision is formed in thesclera, the incision comprising a length extending along a pars plana ofthe eye and a width, the length greater than the width. The container ispositioned in the eye to release the therapeutic agent. The narrowportion of the retention structure is aligned with the elongate incisionsuch that the first longer distance across extends substantially alongthe elongate incision and the second shorter distance across extendssubstantially across the width of the incision.

In many embodiments, the pars plana extends circumferentially along theeye between a choroid of the eye and a pars plicata of the eye andwherein the length of the incision is greater than a distance across thepars plana between the choroid of the eye and the pars plicata of theeye and wherein the length of the incision is oriented to fit theincision within the pars plana of the eye.

In many embodiments, the eye comprises a conjunctiva and wherein theretention structure comprises an extension having a distance acrossgreater than the longer distance of the narrow portion and wherein theextension is positioned between the sclera and the conjunctiva.

In another aspect, embodiments provide a method of treating an eye of apatient. A therapeutic device is provided comprising a reservoir and atherapeutic agent disposed therein.

The container is positioned in the eye to release the therapeutic agent.The narrow portion of the retention structure is aligned with theelongate incision such that the first longer distance across extendssubstantially along the elongate incision and the second shorterdistance across extends substantially across the width of the incision.

In another aspect, embodiments provide a method of treating an eye of apatient. A therapeutic device is provided comprising a container and atherapeutic agent disposed within the container. The therapeutic agentcomprises a half-life within the container of at least about 20 dayswhen implanted. The container is postioned in the eye to release thetherapeutic agent, wherein the eye is treated with the therapeutic agentfor at least about 90 days.

In another aspect, embodiments provide a method of treating an eye of apatient. A therapeutic device is provided comprising a reservoir and atherapeutic agent disposed within the reservoir. The therapeutic agentcomprises a half-life within the reservoir of no more than about 30 dayswhen implanted. The container is positioned in the eye to release thetherapeutic agent, the eye is treated with the therapeutic agent for atleast about 180 days.

In another aspect, embodiments provide a method of treating an eye of apatient. A therapeutic device is provided comprising a reservoir and atherapeutic agent disposed within the reservoir, and the therapeuticagent comprises a half-life within the reservoir when implanted. Thehalf life within the reservoir is substantially greater than acorresponding half-life of the therapeutic agent when injected directlyinto the vitreous. The container is positioned in the eye to release thetherapeutic agent, and the eye is treated with the therapeutic agent forat least about 180 days.

In many embodiments, the therapeutic agent comprises ranibizumab.

In another aspect, embodiments provide a method of manufacturing atherapeutic device to release a therapeutic agent. A gas is measuredcoupled to a porous structure. A container is provided to contain thetherapeutic agent. The porous structure is coupled to the container.

In many embodiments, the gas is measured to determine a release rate ofthe therapeutic agent through the porous structure.

In many embodiments, the gas is measured to determine a resistance toflow of the porous structure.

In many embodiments, the gas is measured with a first pressure at afirst time and a second pressure at a second time.

In many embodiments, the gas is measured with a pressure drop across theporous structure.

In many embodiments, the gas is measured with a volume of gas passedthrough the porous structure per unit time.

In many embodiments, the gas is measured before the porous structure iscoupled to the container.

In many embodiments, the therapeutic device comprises a supportstructure and the gas flow is measured when the porous structure isaffixed to the support structure.

In many embodiments, the gas flow is measured a first time before theporous structure is coupled to the container and the device therapeuticcomprises a support and wherein the gas flow is measured a second timewhen the porous structure is affixed to the support.

In another aspect, embodiments provide a method of treating an eyehaving a vitreous humor. A quantity of a formulation of therapeuticagent is injected into a therapeutic device, and the therapeutic deviceis tuned to receive the quantity.

In another aspect, embodiments provide a method of treating an eyehaving a vitreous humor. A formulation of a therapeutic agent isprovided. The therapeutic agent is capable of treating the eye withbolus injections. The formulation has a corresponding period betweeneach of the bolus injections to treat the eye and each of the bolusinjections comprises a volume of the formulation such that each of thebolus injections corresponds to a range of therapeutic concentrations ofthe agent in the vitreous humor to treat the eye. A therapeutic deviceis provided to treat the eye with an injection of the volume of theformulation into the device, and the device comprises a container havinga chamber to contain a volume of the therapeutic agent and a mechanismto release the therapeutic agent from the chamber to the vitreous humor.The volume of the container and the release mechanism are tuned to treatthe eye with concentrations of the therapeutic agent in the vitreoushumor within the range for an extended time with each injection of thequantity, and the extended time comprises at least about twice theperiod.

In many embodiments, the chamber comprises a substantially fixed volumeand the release rate mechanism comprises a substantially rigid structureto maintain release of the therapeutic agent above the minimuminhibitory concentration for the extended time with each injection of aplurality of injections.

In many embodiments, the release mechanism comprises one or more of aporous frit, a permeable membrane, a semi-permeable membrane, acapillary tube or a tortuous channel, nano-structures, nano-channels orsintered nano-particles.

In many embodiments, the release mechanism comprises the porous frit andwherein the porous frit comprises a porosity, cross sectional area, anda thickness to release the therapeutic agent for the extended time.

In many embodiments, the volume of the container comprises no more thanabout twice the volume of the formulation.

In many embodiments, the volume of the container comprises no more thanthe volume of the formulation.

In many embodiments, a first portion of the injection passes through therelease mechanism and treats the patient when the formulation isinjected and a second portion of the formulation is contained in thechamber when the formulation is injected and the concentration oftherapeutic agent in the vitreous humor is within the range of thetherapeutic concentrations for the extended time comprising at leastabout twice the period.

In many embodiments, the volume of the container comprises less than thevolume of the injected formulation and wherein a first portion of theinjection passes through the release mechanism when the formulation isinjected and a second portion of the formulation is contained in thechamber when the formulation is injected.

In many embodiments, a vent is opened to exchange material disposedwithin the chamber with the injected formulation and wherein the vent isclosed to pass the first portion through the release mechanism.

In many embodiments, the volume and the mechanism are tuned to releasethe therapeutic concentration within the range for the extended timebased on a half life of the therapeutic agent in the vitreous humor ofthe eye. The eye may comprise a human eye and the half life can bedetermined based on the half life of the therapeutic agent in the humaneye. The half life of the therapeutic agent may comprise at least aboutone hour, for example for a therapeutic agent comprising a smallmolecule. The half life of the therapeutic agent may comprise at leastabout four days, for example for a therapeutic agent comprising a largemolecule.

In another aspect, embodiments provide a method of treating an eyehaving a vitreous humor. A therapeutic device is provided having achamber sized to contain a volume of a therapeutic agent and a porousstructure coupled to the chamber. An injector is provided comprising atleast one lumen to inject a formulation of a therapeutic agent, theinjector comprising a valve coupled to the at least one lumen. Thetherapeutic device is coupled to the injector with the at least onelumen extending at least partially into the therapeutic device. A firstportion of the formulation is injected into the chamber when the valveis open to exchange material disposed within the chamber with the firstportion formulation. A second portion of the formulation is injectedwhen the valve is closed to pass formulation through the porousstructure.

In many embodiments, a part of the first portion passes through theporous structure when the valve is closed and the second portion isinjected.

In many embodiments, a part of the second portion passes through theporous structure when the valve is closed and the second portion isinjected.

In another aspect, embodiments provide a therapeutic device for treatingan eye having a vitreous humor. The therapeutic device comprises areservoir and porous structure tuned to release for an exetended timetherapeutic amounts of a therapeutic agent injected into the reservoir.

In many embodiments, the porous structure comprises a release mechanism,and the reservoir volume and the release mechanism are tuned to releasethe therapeutic amounts of the therapeutic agent for the extended timebased on a half life of the therapeutic agent in the vitreous humor ofthe human eye. The half life of the therapeutic agent may comprise atleast about one hour, for example for a therapeutic agent comprising asmall molecule. The half life of the therapeutic agent may comprise atleast about four days, for example for a therapeutic agent comprising alarge molecule.

In another aspect, embodiments provide a method of treating an eyehaving a vitreous humor. The therapeutic device is provided comprising areservoir and porous structure tuned to release therapeutic amounts of atherapeutic agent for an exetended time. A quantity of therapeutic agentis injected into the reservoir, and the therapeutic agent is releasedfrom the tuned reservoir and porous structure for the extended time.

In another aspect, embodiments provide an apparatus to treat an eyehaving a vitreous humor. The apparatus comprises a therapeutic devicecomprising reservoir to contain a therapeutic agent and a porousstructure. An injector has a first chamber and a second chamber and atleast one needle comprising a first lumen and a second lumen, and thefirst chamber coupled to the first lumen to inject the therapeutic agentfrom the first chamber into the reservoir. The second chamber is coupledto the second lumen with a valve disposed therebetween to receivematerial from the reservoir when the valve is open and pass therapeuticagent through the porous structure when the valve is closed.

In another aspect, embodiments provide a method of treating an eyehaving a vitreous humor. A volume of a formulation of Ranibizumab isinjected into a therapeutic device, the volume is within a range fromabout 40 to 60 uL. The concentration of Ranibizumab of the formulationis within a range from about 8 to 12 mg/mL, such that the injectioncomprises a weight Ranibizumab within a range from about 0.4 to about0.6 mg of Ranibizumab. The Ranibizumab is released in therapeuticamounts for an extended time of at least about 4 months.

In many embodiments, the formulation comprises a commercially availableformulation of Lucentis™ and the volume corresponds to a monthly bolusinjection of about 50 uL of Lucentis™ and a concentration of theRanibizumab in the vitreous humor remains at least about 4 ug/mL for theextended time.

In another aspect, embodiments provide a method of treating an eye. Themethod comprises placing a container comprising a reservoir and apenetrable barrier at least partially through a sclera of the eye,wherein the reservoir comprises a fluid. A therapeutic amount of atleast one therapeutic agent is injected into the container. Thetherapeutic amount corresponds to a bolus injection to treat the eye forabout one month and therapeutic quantities of the therapeutic agent arereleased from the container for at least about two months to treat theeye.

In another aspect, embodiments provide a method of treating an eye, theeye having a sclera and a pars plana. A therapeutic device is providedcomprising a drug reservoir, a porous structure and a retentionstructure, the retention structure comprising an elongatecross-sectional profile. An incision is formed through the sclera andextending along the pars plana region. The therapeutic device isadvanced into the sclera with the elongate cross-sectional profilealigned with the incision along the pars plana, and the elongatecross-sectional profile seals the incision when the elongatecross-sectional profile contacts the sclera.

In many embodiments, the alignment structure comprises a conformableflange disposed over the elongate cross-sectional profile and whereinthe conformable flange contacts and upper surface of the sclera when theelongate cross-sectional profile contacts the sclera.

In many embodiments, the eye comprises a conjunctiva and the methodfurther comprises forming a first incision through the conjunctiva at afirst location. The conjunctive is moved to expose the sclera at asecond location. The incision through the sclera is formed at the secondlocation, and the incision through conjunctiva is slid to the firstlocation to cover the implant at the second location and seal theincision.

In another aspect, embodiments provide an apparatus. The apparatuscomprises a therapeutic device comprising a shape changing drugreservoir, a porous structure and a retention structure, and cannula.The therapeutic device is positioned within the cannula.

In many embodiments, the therapeutic device comprises an elongate narrowshape for insertion into the sclera and wherein the device is configuredto expand to a second elongate wide shape for retention in the sclera

In many embodiments, the reservoir comprises a thin elongated shape wheninserted through the sclera and comprises an extended, ballooned shape,when filled with therapeutic agent.

In another aspect, embodiments provide a therapeutic device to treat apatient. The device comprising means for releasing therapeutic amountsof a therapeutic agent for an extended period.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an eye suitable for incorporation of the therapeuticdevice, in accordance with embodiments of the present invention;

FIG. 1A-1 shows a therapeutic device implanted at least partially withinthe sclera of the eye as in FIG. 1;

FIG. 1A-1-1 and 1A-1-2 show a therapeutic device implanted under theconjunctiva and extending through the sclera to release a therapeuticagent into vitreous humor of the eye so as to treat the retina of the,in accordance with embodiments of the present invention;

FIG. 1A-2 shows structures of a therapeutic device configured forplacement in an eye as in FIGS. 1A-1 and 1A-1-1, according toembodiments of the present invention;

FIG. 1A-2-1 shows a therapeutic device loaded into an insertion cannula,in which the device comprises an elongate narrow shape for insertioninto the sclera, and in which the device is configured to expand to asecond elongate wide shape for retention at least partially in thesclera;

FIG. 1A-2-2 shows a therapeutic device comprising a reservoir suitablefor loading in a cannula;

FIG. 1B shows a therapeutic device configured for placement in an eye asin FIG. 1A-1 and 1A-1-1, in accordance with embodiments of the presentinvention;

FIG. 1C shows a therapeutic device configured for placement in an eye asin FIG. 1A-1 and 1A-1-1, in accordance with embodiments of the presentinvention;

FIG. 1C-A shows at least one exit port, according to embodiments of thepresent invention;

FIG. 1C-1 shows a method of removing a binding material, according toembodiments of the present invention;

FIG. 1C-2 and inserting the therapeutic agent with a second inserthaving the TA bound thereon;

FIG. 1C-3 shows syringe being filled with a commercially availableformulation of therapeutic agent for injection into the therapeuticdevice, in accordance with embodiments;

FIG. 1D shows a therapeutic device configured for placement in an eye asin FIG. 1A-1 and 1A-1-1, in which the device comprises a plurality ofchambers and channels connecting the chambers so as to linearize therelease of the therapeutic agent;

FIG. 1E shows a therapeutic device configured for placement in an eye asin FIGS. 1A-1 and 1A-1-1, in which the device comprises a needle stoplocated at the bottom of the therapeutic device;

FIG. 1E-1 shows a therapeutic device configured for placement in an eyeas in FIGS. 1A-1 and 1A-1-1, in which the device comprises a needle stoplocated at the bottom of the therapeutic device and the shape of thedevice encourages the movement of the therapeutic agent within thechamber of the therapeutic device;

FIG. 1E-2 shows a therapeutic device configured for placement in an eyeas in FIGS. 1A-1 and 1A-1-1, in which the device comprises a needle stoplocated in the middle of the therapeutic device;

FIG. 1E-3 shows a therapeutic device configured for placement in an eyeas in FIGS. 1A-1 and 1A-1-1, in which the device comprises a needle stoplocated in the middle of the therapeutic device and the shape of thedevice encourages the movement of the therapeutic agent within thechamber of the therapeutic device;

FIG. 1E-3-1 shows a top view of the therapeutic device configured forplacement in an eye as in FIGS. 1E-3;

FIG. 2 shows an access port suitable for incorporation with thetherapeutic device, in accordance with embodiments of the presentinvention;

FIG. 3A shows a collar suitable for incorporation with the therapeuticdevice, in accordance with embodiments of the present invention;

FIG. 3B shows biocompatible material impregnated with an anti-bacterialagent on the therapeutic device to inhibit bacterial growth along thedevice from the sclera to the vitreous humor;

FIG. 4A shows released fragments of antibodies, and FIG. 4B showsantibody fragments reversibly bound to a substrate, in accordance withembodiments of the present invention;

FIG. 5A shows a therapeutic device coupled to an injector to inserttherapeutic agent into the device;

FIG. 5A-1 shows a therapeutic device coupled to an injector tosimultaneously inject and remove material from the device;

FIG. 5B shows a therapeutic device comprising a micro loop channel;

FIG. 5C1 shows a therapeutic device comprising a tortuous channel;

FIG. 5C2 shows a therapeutic device comprising a coiled channel;

FIG. 5D shows an expandable and contractible structure to retain thetherapeutic agent and an outer rigid casing to couple to the sclera;

FIGS. 5E shows a membrane disposed over an exit port of a therapeuticdevice;

FIG. 5F shows a therapeutic device comprising a tubular membrane clampedonto the therapeutic device;

FIG. 6A1 shows a therapeutic device comprising a container having apenetratable barrier disposed on a first end, a porous structuredisposed on a second end to release therapeutic agent for an extendedperiod, and a retention structure comprising an extension protrudingoutward from the container to couple to the sclera and the conjunctiva;

FIG. 6A-2 shows a therapeutic device as in FIG. 6A comprising a roundeddistal end;

FIG. 6B shows a rigid porous structure configured for sustained releasewith a device as in FIG. 6A;

FIG. 6B-1 shows interconnecting channels extending from a first side toa second side of the porous structure as in FIG. 6B;

FIG. 6B-2 shows a plurality of paths of the therapeutic agent along theinterconnecting channels extending from a first side to a second side ofthe porous structure as in FIGS. 6B and 6B1;

FIG. 6B-3 shows blockage of the openings with a covering and theplurality of paths of the therapeutic agent along the interconnectingchannels extending from a first side to a second side of the porousstructure as in FIGS. 6B and 6B-1;

FIG. 6B-4 shows blockage of the openings with particles and theplurality of paths of the therapeutic agent along the interconnectingchannels extending from a first side to a second side of the porousstructure as in FIGS. 6B and 6B-1;

FIG. 6B-5 shows an effective cross-sectional size and area correspondingto the plurality of paths of the therapeutic agent along theinterconnecting channels extending from a first side to a second side ofthe porous structure as in FIGS. 6B and 6B-1;

FIG. 6C shows a rigid porous structure as in FIG. 6B incorporated into ascleral tack;

FIG. 6D, shows a rigid porous structure as in FIG. 6B coupled with areservoir for sustained release;

FIG. 6E shows a rigid porous structure as in FIG. 6B comprising a hollowbody or tube for sustained release;

FIG. 6F shows a rigid porous structure as in FIG. 6B comprising anon-linear helical structure for sustained release;

FIG. 6G shows porous nanostructures, in accordance with embodiments;

FIG. 7 shows a therapeutic device coupled to an injector that removesmaterial from the device and injects therapeutic agent into the device,according to embodiments;

FIG. 7A shows a therapeutic device comprising a porous structure and apenetrable barrier as in FIG. 6E, with the penetrable barrier coupled toan injector to inject and remove material from the device, in accordancewith embodiments;

FIG. 7A1 shows a therapeutic device coupled to an injector needlecomprising a stop that positions the distal end of the needle near theproximal end of the device to flush the reservoir with ejection ofliquid formulation through the porous frit structure, in accordance withembodiments;

FIG. 7A2 shows a therapeutic device comprising a penetrable barriercoupled to an injector to inject and remove material from the devicesuch that the liquid in the reservoir is exchanged with the injectedformulation, in accordance with embodiments;

FIG. 7B-1 shows a side cross-sectional view of a therapeutic devicecomprising a retention structure having a cross-section sized to fit inan elongate incision, in accordance with embodiments;

FIG. 7B-2 shows an isometric view of the therapeutic device as in FIG.7B-1;

FIG. 7B-3 shows a top view of the therapeutic device as in FIG. 7B-1;

FIG. 7B-4 shows a side cross sectional view along the short side of theretention structure of the therapeutic device as in FIG. 7B-1;

FIG. 7B-5 shows a bottom view of the therapeutic device as in FIG. 7B-1implanted in the sclera;

FIG. 7B-5A shows a cutting tool comprising a blade having a widthcorresponding to the perimeter of the barrier and the perimeter of thenarrow retention structure portion;

FIGS. 7B-6A and 7B-6B show distal cross-sectional view and a proximalcross-sectional view, respectively, of a therapeutic device comprisingan elongate and non-circular cross-sectional size, in accordance withembodiments;

FIG. 7B-6C shows an isometric view of the therapeutic device having aretention structure with an elongate cross-sectional size, in accordancewith embodiments;

FIG. 7B-6D shows a distal end view of the therapeutic device as in FIG.7B-6C;

FIG. 7B-6E1 shows a side view of the short axis of the narrow neckportion of the therapeutic device as in FIG. 7B-6C;

FIG. 7B-6E2 shows a side view of the long axis of the narrow neckportion of the therapeutic device as in FIG. 7B-6C;

FIG. 7B-6F shows a proximal view view of the therapeutic device as inFIGS. 7B-6C;

FIG. 7B-6G to FIG. 7B-6I show exploded assembly drawings for thetherapeutic device as in FIGS. 7B-6C to 7B-6F;

FIG. 7C-1 shows an expandable therapeutic device comprising anexpandable barrier material and support in an expanded configuration forextended release of the therapeutic agent, in accordance withembodiments;

FIG. 7C-1A shows the distal end portion of the support 160S as in FIG.7C-1;

FIG. 7C-1B shows the support 160S disposed inside the barrier 160, inaccordance with embodiments;

FIG. 7C-1C shows the support 160S disposed along the inner surface ofthe barrier 160, in accordance with embodiments;

FIG. 7C-2 shows the expandable therapeutic device as in FIG. 7C1 in anarrow profile configuration;

FIG. 7C-3 shows the expandable therapeutic device as in FIG. 7C1 in anexpanded profile configuration;

FIGS. 7C-4A and 7C-4B show an expandable retention structure, inaccordance with embodiments;

FIG. 7D shows a therapeutic device comprising a porous structurepositioned in an eye to deliver a therapeutic agent to a target locationon the retina, in accordance with embodiments

FIG. 7E shows a therapeutic device comprising a porous structure locatedon the device to deliver a therapeutic agent to one or more of theciliary body or the trabecular meshwork when positioned in the eye, inaccordance with embodiments;

FIG. 7F shows therapeutic device 100 comprising porous structure 150oriented to release the therapeutic agent away from the lens and towardthe retina, in accordance with embodiments;

FIG. 7G shows a kit comprising a placement instrument, a container, anda therapeutic device within the container, in accordance withembodiments;

FIG. 8 show reservoirs with exit ports of defined diameters fabricatedfrom 1 mL syringes with Luer-Lok™ tips and needles of varying diameter,in accordance with embodiments;

FIG. 8-1 shows the needles attached to syringes as in FIG. 8;

FIG. 8-2 shows the reservoirs placed into vials;

FIG. 9 shows cumulative release through the needles of varying diameter;

FIG. 10 shows release rate as a function of area;

FIG. 11 shows a reservoir with a porous membrane fabricated by cuttingoff the Luer-Lok tip on a 1 mL syringe;

FIG. 11-1 shows the delivery rates from two replicates of a reservoir asin FIG. 11;

FIG. 12 shows the cumulative release of fluorescein through cut-offneedles;

FIG. 13 shows the cumulative release of BSA protein through a sinteredporous titanium cylinder;

FIG. 13-1 shows the measured cumulative release of BSA of FIG. 133measured to 180 days;

FIG. 14 shows the cumulative release of BSA protein through a maskedsintered porous titanium cylinder at Condition 1, in accordance withexperimental embodiments;

FIG. 15 shows cumulative release of BSA protein through a maskedsintered porous titanium cylinder at Condition 2, in accordance withexperimental embodiments;

FIG. 16 shows cumulative release of BSA protein through a maskedsintered porous titanium cylinder at Condition 3, in accordance withexperimental embodiments;;

FIG. 17 shows cumulative release of BSA through 0.1 media grade sinteredporous stainless steel cylinder;

FIG. 18A shows cumulative release of BSA through 0.2 media gradesintered porous stainless steel cylinder;

FIG. 18B shows cumulative release of BSA through 0.2 media gradesintered porous stainless steel cylinder for 180 days;

FIG. 19A compares calculated Lucentis™ pharmacokinetics profiles to thepharmacokinetics profiles predicted for the device in Example 8;

FIG. 19B shows determined concentrations of ranibizumab in the vitreoushumor for a a first 50 uL Lucentis™ injection into a 25 uL reservoir ofthe device and a second 50 uL injection at 90 days, in accordance withembodiments;

FIG. 19C shows determined concentrations of ranibizumab in the vitreoushumor for a first 50 uL Lucentis™ injection into a 32 uL reservoir ofthe device and a second 50 uL injection at 90 days, in accordance withembodiments;

FIG. 19D shows determined concentrations of ranibizumab in the vitreoushumor for a first 50 uL Lucentis™ injection into a 50 uL reservoir ofthe device and a second 50 uL injection at 90 days, in accordance withembodiments;

FIG. 19E shows determined concentrations of ranibizumab in the vitreoushumor for a first 50 uL Lucentis™ injection into a 50 uL reservoir ofthe device and a second 50 uL injection at 130 days, in accordance withembodiments;

FIG. 19F shows determined concentrations of ranibizumab in the vitreoushumor for a 50 uL Lucentis™ injection into a 50 uL device having arelease rate index of 0.05, in accordance with embodiments;

FIG. 19G shows determined concentrations of ranibizumab in the vitreoushumor for a 50 uL Lucentis™ injection into a 75 uL device having arelease rate index of 0.05, in accordance with embodiments;

FIG. 19H shows determined concentrations of ranibizumab in the vitreoushumor for a 50 uL Lucentis™ injection into a 100 uL device having arelease rate index of 0.05, in accordance with embodiments;

FIG. 191 shows determined concentrations of ranibizumab in the vitreoushumor for a 50 uL Lucentis™ injection into a 125 uL device having arelease rate index of 0.05, in accordance with embodiments;

FIG. 19J shows determined concentrations of ranibizumab in the vitreoushumor for a 50 uL Lucentis™ injection into a 150 uL device having arelease rate index of 0.05, in accordance with embodiments;

FIG. 19K shows determined concentrations of ranibizumab in the vitreoushumor for a 50 uL Lucentis™ injection into a 100 uL device having arelease rate index of 0.1, in accordance with embodiments;

FIG. 19L shows determined concentration profiles of ranibizumab in thevitreous humor for a 50 uL Lucentis™ injection into a 125 uL reservoirdevice having a release rate index of 0.105, in accordance withembodiments;

FIG. 19M shows determined concentration profiles of ranibizumab in thevitreous humor for a 50 uL Lucentis™ injection into a 125 uL reservoirdevice having a release rate index of 0.095, in accordance withembodiments;

FIG. 19N shows determined concentration profiles of ranibizumab in thevitreous humor for a 50 uL Lucentis™ injection into a 125 uL reservoirdevice having a release rate index of 0.085, in accordance withembodiments;

FIG. 19O shows determined concentration profiles of ranibizumab in thevitreous humor for a 50 uL Lucentis™ injection into a 125 uL reservoirdevice having a release rate index of 0.075, in accordance withembodiments;

FIG. 19P shows determined concentration profiles of ranibizumab in thevitreous humor for a 50 uL Lucentis™ injection into a 125 uL reservoirdevice having a release rate index of 0.065, in accordance withembodiments;

FIG. 19Q shows determined concentrations of ranibizumab in the vitreoushumor for a 10 uL concentrated Lucentis™ (40 mg/mL) injection into a 10uL device having a release rate index of 0.01 and in which theranibizumab has a half life in the vitreous humor of about nine days, inaccordance with embodiments;

FIG. 19R shows determined concentrations of ranibizumab in the vitreoushumor for a 10 uL concentrated Lucentis™ (40 mg/mL) injection into a 10uL device having a release rate index of 0.01 and in which theranibizumab has a half life in the vitreous humor of about five days, inaccordance with embodiments;

FIG. 19S shows determined concentrations of ranibizumab in the vitreoushumor for a 10 uL standard Lucentis™ (10 mg/mL) injection into a 10 uLdevice having a release rate index of 0.01 and in which the ranibizumabhas a half life in the vitreous humor of about nine days, in accordancewith embodiments;

FIG. 19T shows determined concentrations of ranibizumab in the vitreoushumor for a 10 uL standard Lucentis™ (10 mg/mL) injection into a 10 uLdevice having a release rate index of 0.01 and in which the ranibizumabhas a half life in the vitreous humor of about five days, in accordancewith embodiments;

FIG. 20 shows a calculated time release profile of a therapeutic agentsuspension in a reservoir, in accordance with embodiments.

FIG. 21 shows cumulative release for Avastin™ with therapeutic devicescomprising substantially similar porous frit structures and a 16 uLreservoir and a 33 uL reservoir;

FIG. 22A shows cumulative release for Avastin™ with porous fritstructures having a thickness of 0.049″;

FIG. 22B-1 shows cumulative release for Avastin™ with porous fritstructures having a thickness of 0.029″;

FIG. 22B-2 shows rate of release for Avastin™ with porous fritstructures having a thickness of 0.029″ as in FIG. 22B-1;

FIG. 23A shows cumulative release for Avastin™ with a reservoir volumeof 20 uL;

FIG. 23A-1 shows cumulative release to about 90 days for Avastin™ with areservoir volume of 20 uL as in FIG. 23A;

FIG. 23B shows rate of release as in FIG. 23A;

FIG. 23B-1 shows rate of release as in FIG. 23A-1;

FIG. 24A shows cumulative release for Avastin™ with a 0.1 media gradeporous frit structure;

FIG. 24A-1 shows cumulative release to about 90 days release forAvastin™ with a 0.1 media grade porous frit structure as in FIG. 24A;

FIG. 24B shows rates of release of the devices as in FIG. 24A;

FIG. 24B-1 shows rates of release of the devices as in FIG. 24A-1;

FIG. 25A shows cumulative release for fluorescein through a 0.2 mediagrade porous frit structure;

FIG. 25A-1 shows cumulative release to about 90 days for fluoresceinthrough a 0.2 media grade porous frit structure as in FIG. 25A;

FIG. 25B shows rates of release of the devices as in FIG. 25A;

FIG. 25B-1 shows rates of release of the devices as in FIG. 25A-1;

FIG. 25C shows cumulative release to about thirty days for Lucentis™through a 0.2 media grade porous frit structure having a diameter of0.038 in and a length (thickness) of 0.029 in.;

FIG. 25D shows rates of release of the devices as in FIG. 25C;

FIG. 25E shows cumulative release to about thirty days for Lucentis™ for30 uL devices having a RRI's from about 0.015 to about 0.090;

FIG. 25F shows rates of release of the devices as in FIG. 25E;

FIGS. 26A and 26B show scanning electron microscope images fromfractured edges of porous frit structures so as to show the structure ofthe porous structure to release the therapeutic agent, in accordancewith embodiments;

FIGS. 27A and 27B show scanning electron microscope images from surfacesof porous frit structures, in accordance with embodiments;

FIG. 28 shows a pressure decay test and test apparatus for use with aporous structure so as to identify porous frit structures suitable foruse with therapeutic devices in accordance with embodiments describedherein;

FIG. 29 shows a pressure flow test and test apparatus suitable for usewith a porous structure so as to identify porous frit structuressuitable for use with therapeutic devices in accordance with embodimentsdescribed herein;

FIG. 30A-1 shows an example of an OCT macular cube OCT image used toidentify a region of interest (black arrow) and determine the responseto treatment;

FIGS. 30B-1, 30B-2 and 30B-3 show an example of a series of OCT scanimages assured at pre-injection, one day post-injection and one weekpost-injection, respectively, of sections of the region of interest; and

FIGS. 31A and 31B shows experimental implantation of therapeutic deviceinto the pars plana region 25 of a rabbit eye with visualization of thedevice sealing the elongate incision under the flange and dark fieldvisualization of the implanted thereapeutic device.

DETAILED DESCRIPTION OF THE INVENTION

Although specific reference is made to the delivery of macromoleculescomprising antibodies or antibody fragments to the posterior segment ofthe eye, embodiments of the present invention can be used to delivermany therapeutic agents to many tissues of the body. For example,embodiments of the present invention can be used to deliver therapeuticagent for an extended period to one or more of the following tissues:intravascular, intra articular, intrathecal, pericardial, intraluminaland gut.

Embodiments of the present invention provide sustained release of atherapeutic agent to the posterior segment of the eye or the anteriorsegment of the eye, or combinations thereof. Therapeutic amounts of atherapeutic agent can be released into the vitreous humor of the eye,such that the therapeutic agent can be transported by at least one ofdiffusion or convection to the retina or other ocular tissue, such asthe choroid or ciliary body, for therapeutic effect.

As used herein the release rate index encompasses (PA/FL) where Pcomprises the porosity, A comprises an effective area, F comprises acurve fit parameter corresponding to an effective length and L comprisesa length or thickness of the porous structure. The units of the releaserate index (RRI) comprise units of mm unless indicated otherwise and canbe determine by a person of ordinary skill in the art in accordance withthe teachings described hereon.

As used herein, sustained release encompasses release of therapeuticamounts of an active ingredient of a therapeutic agent for an extendedperiod of time. The sustained release may encompass first order releaseof the active ingredient, zero order release of the active ingredient,or other kinetics of release such as intermediate to zero order andfirst order, or combinations thereof

As used herein a therapeutic agent referred to with a trade nameencompasses one or more of the formulation of the therapeutic agentcommercially available under the tradename, the active ingredient of thecommercially available formulation, the generic name of the activeingredient, or the molecule comprising the active ingredient.

As used herein, similar numerals indicate similar structures and/orsimilar steps.

The therapeutic agent may be contained within a chamber of a container,for example within a reservoir comprising the container and chamber. Thetherapeutic agent may comprise a formulation such as solution oftherapeutic agent, a suspension of a therapeutic agent or a dispersionof a therapeutic agent, for example. Examples of therapeutic agentssuitable for use in accordance with embodiments of the therapeuticdevice are described herein, for example with reference to Table 1Abelow and elsewhere.

The therapeutic agent may comprise a macromolecule, for example anantibody or antibody fragment. The therapeutic macromolecule maycomprise a VEGF inhibitor, for example commercially available Lucentis™.The VEGF (Vascular Endothelial Growth Factor) inhibitor can causeregression of the abnormal blood vessels and improvement of vision whenreleased into the vitreous humor of the eye. Examples of VEGF inhibitorsinclude Lucentis™, Avastin™, Macugen™, and VEGF Trap.

The therapeutic agent may comprise small molecules such as of acorticosteroid and analogues thereof. For example, the therapeuticcorticosteroid may comprise one or more of trimacinalone, trimacinaloneacetonide, dexamethasone, dexamethasone acetate, fluocinolone,fluocinolone acetate, or analogues thereof. Alternatively or incombination, he small molecules of therapeutic agent may comprise atyrosine kinase inhibitor comprising one or more of axitinib, bosutinib,cediranib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib,lestaurtinib, nilotinib, semaxanib, sunitinib, toceranib, vandetanib, orvatalanib, for example.

The therapeutic agent may comprise an anti-VEGF therapeutic agent.Anti-VEGF therapies and agents can be used in the treatment of certaincancers and in age-related macular degeneration. Examples of anti-VEGFtherapeutic agents suitable for use in accordance with the embodimentsdescribed herein include one or more of monoclonal antibodies such asbevacizumab (Avastin™) or antibody derivatives such as ranibizumab(Lucentis™), or small molecules that inhibit the tyrosine kinasesstimulated by VEGF such as lapatinib (Tykerb™), sunitinib (Sutent™),sorafenib (Nexavar™), axitinib, or pazopanib.

The therapeutic agent may comprise a therapeutic agent suitable fortreatment of dry AMD such as one or more of Sirolimus™ (Rapamycin),Copaxone™ (Glatiramer Acetate), Othera™, Complement C5aR blocker,Ciliary Neurotrophic Factor, Fenretinide or Rheopheresis.

The therapeutic agent may comprise a therapeutic agent suitable fortreatment of wet AMD such as one or more of REDD14NP (Quark), Sirolimus™(Rapamycin), ATG003; Regeneron™ (VEGF Trap) or complement inhibitor(POT-4).

The therapeutic agent may comprise a kinase inhibitor such as one ormore of bevacizumab (monoclonal antibody), BIBW 2992 (small moleculetargeting EGFR/Erb2), cetuximab (monoclonal antibody), imatinib (smallmolecule), trastuzumab (monoclonal antibody), gefitinib (smallmolecule), ranibizumab (monoclonal antibody), pegaptanib (smallmolecule), sorafenib (small molecule), dasatinib (small molecule),sunitinib (small molecule), erlotinib (small molecule), nilotinib (smallmolecule), lapatinib (small molecule), panitumumab (monoclonalantibody), vandetanib (small molecule)or E7080 (targeting VEGFR2/VEGFR2,small molecule commercially available from Esai, Co.)

The amount of therapeutic agent within the therapeutic device maycomprise from about 0.01 mg to about 1 mg, for example Lucentis™, so asto provide therapeutic amounts of the therapeutic agent for the extendedtime, for example at least 30 days. The extended time may comprise atleast 90 days or more, for example at least 180 days or for example atleast 1 year, at least 2 years or at least 3 years or more. The targetthreshold therapeutic concentration of a therapeutic agent such asLucentis™ in the vitreous may comprise at least a therapeuticconcentration of 0.1 ug/mL. For example the target thresholdconcentration may comprise from about 0.1 ug/mL to about 5 ug/mL for theextended time, where the upper value is based upon calculations shown inExample 9 using published data. The target threshold concentration isdrug dependent and thus may vary for other therapeutic agents.

The delivery profile may be configured in many ways to obtain atherapeutic benefit from the sustained release device. For example, anamount of the therapeutic agent may be inserted into the container atmonthly intervals so as to ensure that the concentration of therapeuticdevice is above a safety protocol or an efficacy protocol for thetherapeutic agent, for example with monthly or less frequent injectionsinto the container. The sustained release can result in an improveddelivery profile and may result in improved results. For example, theconcentration of therapeutic agent may remain consistently above athreshold amount, for example 0.1 ug/mL, for the extended time.

The insertion method may comprise inserting a dose into the container ofthe therapeutic device. For example, a single injection of Lucentis™ maybe injected into the therapeutic device.

The duration of sustained delivery of the therapeutic agent may extendfor twelve weeks or more, for example four to six months from a singleinsertion of therapeutic agent into the device when the device isinserted into the eye of the patient.

The therapeutic agent may be delivered in many ways so as to provide asustained release for the extended time. For example, the therapeuticdevice may comprise a therapeutic agent and a binding agent. The bindingagent may comprise small particles configured to couple releasably orreversibly to the therapeutic agent, such that the therapeutic agent isreleased for the extended time after injection into the vitreous humor.The particles can be sized such that the particles remain in thevitreous humor of the eye for the extended time.

The therapeutic agent may be delivered with a device implanted in theeye. For example, the drug delivery device can be implanted at leastpartially within the sclera of the eye, so as to couple the drugdelivery device to the sclera of the eye for the extended period oftime. The therapeutic device may comprise a drug and a binding agent.The drug and binding agent can be configured to provide the sustainedrelease for the extended time. A membrane or other diffusion barrier ormechanism may be a component of the therapeutic device to release thedrug for the extended time.

The lifetime of the therapeutic device and number of injections can beoptimized for patient treatment. For example, the device may remain inplace for a lifetime of 30 years, for example with AMD patients fromabout 10 to 15 years. For example, the device may be configured for animplantation duration of at least two years, with 8 injections (onceevery three months) for sustained release of the therapeutic agent overthe two year duration. The device may be configured for implantation ofat least 10 years with 40 injections (once every three months) forsustained release of the therapeutic agent.

The therapeutic device can be refilled in many ways. For example, thetherapeutic agent can be refilled into the device in the physician'soffice.

The therapeutic device may comprise many configurations and physicalattributes, for example the physical characteristics of the therapeuticdevice may comprise at least one of a drug delivery device with asuture, positioning and sizing such that vision is not impaired, andbiocompatible material. The device may comprise a reservoir capacityfrom about 0.005 cc to about 0.2 cc, for example from about 0.01 cc toabout 0.1 cc, and a device volume of no more than about 2 cc. Avitrectomy may be performed for device volumes larger than 0.1 cc. Thelength of the device may not interfere with the patient's vision and canbe dependent on the shape of the device, as well as the location of theimplanted device with respect to the eye. The length of the device mayalso depend on the angle in which the device is inserted. For example, alength of the device may comprise from about 4 to 6 mm. Since thediameter of the eye is about 24 mm, a device extending no more thanabout 6 mm from the sclera into the vitreous may have a minimal effecton patient vision.

Embodiments may comprise many combinations of implanted drug deliverydevices. The therapeutic device may comprise a drug and binding agent.The device may also comprise at least one of a membrane, an opening, adiffusion barrier, a diffusion mechanism so as to release therapeuticamounts of therapeutic agent for the extended time.

FIG. 1 shows an eye 10 suitable for incorporation of the therapeuticdevice. The eye has a cornea 12 and a lens 22 configured to form animage on the retina 26. The cornea can extend to a limbus 14 of the eye,and the limbus can connect to a sclera 24 of the eye. A conjunctiva 16of the eye can be disposed over the sclera. The lens can accommodate tofocus on an object seen by the patient. The eye has an iris 18 that mayexpand and contract in response to light. The eye also comprises achoroid 28 disposed the between the sclera 24 and the retina 26. Theretina comprises the macula 32. The eye comprises a pars plana 25, whichcomprises an example of a region of the eye suitable for placement andretention, for example anchoring, of the therapeutic device 100 asdescribed herein. The pars plana region may comprise sclera andconjuncitva disposed between the retina and cornea. The therapeuticdevice can be positioned so as to extend from the pars plana region intothe vitreous humor 30 to release the therapeutic agent. The therapeuticagent can be released into the vitreous humor 30, such that thetherapeutic agent arrives at the retina and choroids for therapeuticeffect on the macula. The vitreous humor of the eye comprises a liquiddisposed between the lens and the retina. The vitreous humor maycomprise convection currents to deliver the therapeutic agent to themacula.

FIG. 1A-1 shows a therapeutic device 100 implanted at least partiallywithin the sclera 24 of the eye 10 as in FIG. 1. The therapeutic devicemay comprise a retention structure, for example a protrusion, to couplethe device to the sclera. The therapeutic device may extend through thesclera into vitreous humor 30, such that the therapeutic device canrelease the therapeutic agent into the vitreous humor.

FIGS. 1A-1-1 and 1A-1-2shows a therapeutic device 100 implanted underthe conjunctiva 16 and extending through the sclera 24 to release atherapeutic agent 110 into vitreous humor 30 of the eye 10 so as totreat the retina of the eye. The therapeutic device 100 may comprise aretention structure 120 such as a smooth protrusion configured forplacement along the sclera and under the conjunctiva, such that theconjunctiva can cover the therapeutic device and protect the therapeuticdevice 100. When the therapeutic agent 110 is inserted into the device100, the conjunctiva may be lifted away, incised, or punctured with aneedle to access the therapeutic device. The eye may comprise aninsertion of the tendon 27 of the superior rectus muscle to couple thesclera of the eye to the superior rectus muscle. The device 100 may bepositioned in many locations of the pars plana region, for example awayfrom tendon 27 and one or more of posterior to the tendon, posterior tothe tendon, under the tendon, or with nasal or temporal placement of thetherapeutic device.

While the implant can be positioned in the eye in many ways, work inrelation to embodiments suggests that placement in the pars plana regioncan release therapeutic agent into the vitreous to treat the retina, forexample therapeutic agent comprising an active ingredient composed oflarge molecules.

Therapeutic agents 110 suitable for use with device 100 includes manytherapeutic agents, for example as listed in Table 1A, herein below. Thetherapeutic agent 110 of device 100 may comprise one or more of anactive ingredient of the therapeutic agent, a formulation of thetherapeutic agent, a commercially available formulation of thetherapeutic agent, a physician prepared formulation of therapeuticagent, a pharmacist prepared formulation of the therapeutic agent, or acommercially available formulation of therapeutic agent having anexcipient. The therapeutic agent may be referred to with generic name ora trade name, for example as shown in Table 1A.

The therapeutic device 100 can be implanted in the eye to treat the eyefor as long as is helpful and beneficial to the patient. For example thedevice can be implanted for at least about 5 years, such as permanentlyfor the life of the patient. Alternatively or in combination, the devicecan be removed when no longer helpful or beneficial for treatment of thepatient.

FIG. 1A-2 shows structures of therapeutic device 100 configured forplacement in an eye as in FIGS. 1A-1, 1A-1-1 and 1A-1-2. The device maycomprise retention structure 120 to couple the device 100 to the sclera,for example a protrusion disposed on a proximal end of the device. Thedevice 100 may comprise a container 130 affixed to the retentionstructure 120. An active ingredient, for example therapeutic agent 110,can be contained within a reservoir 140, for example a chamber 132defined by a container 130 of the device. The container 130 may comprisea porous structure 150 comprising a porous material 152, for example aporous glass frit 154, and a barrier 160 to inhibit release of thetherapeutic agent, for example non-permeable membrane 162. Thenon-permeable membrane 162 may comprise a substantially non-permeablematerial 164. The non-permeable membrane 162 may comprise an opening 166sized to release therapeutic amounts of the therapeutic agent 110 forthe extended time. The porous structure 150 may comprise a thickness150T and pore sizes configured in conjunction with the opening 166 so asto release therapeutic amounts of the therapeutic agent for the extendedtime. The container 130 may comprise reservoir 140 having a chamber witha volume 142 sized to contain a therapeutic quantity of the therapeuticagent 110 for release over the extended time. The device may comprise aneedle stop 170. Proteins in the vitreous humor may enter the device andcompete for adsorption sites on the porous structure and thereby maycontribute to the release of therapeutic agent. The therapeutic agent110 contained in the reservoir 140 can equilibrate with proteins in thevitreous humor, such that the system is driven towards equilibrium andthe therapeutic agent 110 is released in therapeutic amounts.

The non-permeable membrane 162, the porous material 152, the reservoir140, and the retention structure 120, may comprise many configurationsto deliver the therapeutic agent 110. The non-permeable membrane 162 maycomprise an annular tube joined by a disc having at least one openingformed thereon to release the therapeutic agent. The porous material 152may comprise an annular porous glass frit 154 and a circular enddisposed thereon. The reservoir 140 may be shape-changing for ease ofinsertion, i.e. it may assume a thin elongated shape during insertionthrough the sclera and then assume an extended, ballooned shape, once itis filled with therapeutic agent.

The porous structure 150 can be configured in many ways to release thetherapeutic agent in accordance with an intended release profile. Forexample, the porous structure may comprise a porous structure having aplurality of openings on a first side facing the reservoir and aplurality of openings on a second side facing the vitreous humor, with aplurality of interconnecting channels disposed therebetween so as tocouple the openings of the first side with the openings of the secondside, for example a sintered rigid material. The porous structure 150may comprise one or more of a permeable membrane, a semi-permeablemembrane, a material having at least one hole disposed therein,nano-channels, nano-channels etched in a rigid material, laser etchednano-channels, a capillary channel, a plurality of capillary channels,one or more tortuous channels, tortuous microchannels, sinterednano-particles, an open cell foam or a hydrogel such as an open cellhydrogel.

FIG. 1A-2-1 shows therapeutic device 100 loaded into an insertioncannula 210 of an insertion apparatus 200, in which the device 100comprises an elongate narrow shape for insertion into the sclera, and inwhich the device is configured to expand to a second elongate wide shapefor retention at least partially in the sclera;

FIG. 1A-2-2 shows a therapeutic device 100 comprising reservoir 140suitable for loading in a cannula, in which the reservoir 140 comprisesan expanded configuration.

FIG. 1B shows therapeutic device 100 configured for placement in an eyeas in FIG. 1A-1 and 1A-1-1. The device comprises retention structure 120to couple to the sclera, for example flush with the sclera, and thebarrier 160 comprises a tube 168. An active ingredient 112 comprisingthe therapeutic agent 110 is contained within tube 168 comprisingnon-permeable material 164. A porous material 152 is disposed at thedistal end of the tube 168 to provide a sustained release of thetherapeutic agent at therapeutic concentrations for the extended period.The non-permeable material 164 may extend distally around the porousmaterial 152 so as to define an opening to couple the porous material152 to the vitreous humor when the device is inserted into the eye.

The tube 168 and retention structure 120 may be configured to receive aglass rod, which is surface treated, and the glass rod can be injectedwith therapeutic agent. When the therapeutic agent has finished elutionfor the extended time, the rod can be replaced with a new rod.

The device 100 may comprise therapeutic agent and a carrier, for examplea binding medium comprising a binding agent to deliver the therapeuticagent. The therapeutic agent can be surrounded with a column comprisinga solid support that is eroded away.

FIG. 1C shows a therapeutic device configured for placement in an eye asin FIG. 1A-1 and 1A-1-1. A binding medium 192 comprising a binding agent190 such as glass wool may be loaded with therapeutic agent 110 prior toinjection into the device through an access port 180. The device 100 maycomprise binding, leak, and barrier functions to deliver the therapeuticagent for the extended time. The binding medium 192 and therapeuticagent 110 can be aspirated to replace the binding medium and therapeuticagent. The binding medium can be at least one of flushed or replacedwhen at least majority of the therapeutic agent has been released, suchthat additional therapeutic agent can be delivered from a second,injected binding medium comprising therapeutic agent. A membrane 195 canbe disposed over the periphery of the therapeutic device 100. Themembrane 195 may comprise methylcellulose, regenerated cellulose,cellulose acetate, nylon, polycarbonate, poly(tetrafluoroethylene)(PTFE), polyethersulfone, and polyvinylidene difluoride (PVDF). Thetherapeutic device may comprise barrier 160 shaped such that opening 166comprises an exit port. The therapeutic agent may be released through atleast one of a diffusion mechanism or convection mechanism. The number,size, and configuration of exit ports may determine the release rate ofthe therapeutic agent. The exit port may comprise a convection port, forexample at least one of an osmotically driven convection port or aspring driven convection port. The exit port may also comprise a tubularpath to which the therapeutic agent may temporarily attach, and then bereleased under certain physical or chemical conditions.

FIG. 1C-A shows at least one exit port 167, the exit port can bedisposed on the device 100 to allow liquid to flow from inside thedevice outward, for example when fluid is injected into an injectionport 182 of the device or when an insert such as a glass frit isinserted into the device. The therapeutic device may comprise an accessport 180 for injection and/or removal, for example a septum.Additionally or in the alternative, when the therapeutic device isrefilled, the contents of the device may be flushed into the vitreous ofthe eye.

FIG. 1C-1 shows a method of removing a binding agent 194. A needle 189coupled to a syringe 188 of an injector 187 can be inserted into anaccess port 180 of the therapeutic device 100. The binding agent 194 canbe aspirated with a needle.

FIG. 1C-2 shows a method of inserting the therapeutic agent 110 with asecond binding agent 190 having the therapeutic agent 110 bound thereon.The therapeutic agent can be injected into a container 130 of the devicefor sustained release over the extended time.

FIG. 1C-3 shows syringe being filled with a formulation of therapeuticagent for injection into the therapeutic device. The needle 189 coupledto syringe 188 of injector 187 can be used to draw therapeutic agent 110from a container 110C. The container 110C may comprise a commerciallyavailable container, such as a bottle with a septum, a single dosecontainer, or a container suitable for mixing formulations. A quantity110V of therapeutic agent 110 can be drawn into injector 187 forinjection into the therapeutic device 100 positioned within the eye. Thequantity 110V may comprise a predetermined quantity, for example basedon the volume of the container of the therapeutic device 110 and anintended injection into the vitreous humor. The example the quantity110V may exceed the volume of the container so as to inject a firstportion of quantity 110V into the vitreous humor through the therapeuticdevice and to contain a second portion of quantity 110V within thecontainer of the therapeutic device 110. Container 110C may comprise aformulation 110F of the therapeutic agent 110. The formulation 110F maycomprise a commercially available formulations of therapeutic agent, forexample therapeutic agents as described herein and with reference toTable 1A. Non-limiting examples of commercially available formulationsthat may be suitable for use in accordance with the embodimentsdescribed herein include Lucentis™ and Triamcinolone, for example. Theformulation 110F may be a concentrated or diluted formulation of acommercially available therapeutic agent, for example Avastin™. Theosmolarity and tonicity of the vitreous humor can be within a range fromabout 290 to about 320. For example, a commercially availableformulation of Avastin™ may be diluted so as to comprise a formulationhaving an osmolarity and tonicity substantially similar to theosmolarity and tonicity of the vitreous humor, for example within arange from about 280 to about 340, for example about 300 mOsm. While thetherapeutic agent 110 may comprise an osmolarity and tonicitysubstantially similar to the vitreous humor, the therapeutic agent 110may comprise a hyper osmotic solution relative to the vitreous humor ora hypo osmotic solution relative to the vitreous humor. A person orordinary skill in the art can conduct experiments based on the teachingsdescribed herein so as to determine empirically the formulation andosmolarity of the therapeutic agent to provide release of therapeuticagent for an extended time.

For example, in the United States of America, Lucentis™ (activeingredient ranibizumab) is supplied as a preservative-free, sterilesolution in a single-use glass vial designed to deliver 0.05 mL of 10mg/mL Lucentis™ aqueous solution with 10 mM histidine HCl, 10%α,α-trehalose dihydrate, 0.01% polysorbate 20, at pH 5.5. In Europe, theLucentis™ formulation can be substantially similar to the formulation ofthe United States.

For example, the sustained release formulation of Lucentis™ indevelopment by Genentech and/or Novartis, may comprise the therapeuticagent injected in to the device 100. The sustained release formulationmay comprise particles comprising active ingredient.

For example, in the United States, Avastin™ (bevacizumab) is approved asan anticancer drug and in clinical trials are ongoing for AMD. Forcancer, the commercial solution is a pH 6.2 solution for intravenousinfusion. Avastin™ is supplied in 100 mg and 400 mg preservative-free,single-use vials to deliver 4 mL or 16 mL of Avastin™ (25 mg/mL). The100 mg product is formulated in 240 mg α,α-trehalose dihydrate, 23.2 mgsodium phosphate (monobasic, monohydrate), 4.8 mg sodium phosphate(dibasic, anhydrous), 1.6 mg polysorbate 20, and Water for Injection,USP. The 400 mg product is formulated in 960 mg α,α-trehalose dihydrate,92.8 mg sodium phosphate (monobasic, monohydrate), 19.2 mg sodiumphosphate (dibasic, anhydrous), 6.4 mg polysorbate 20, and Water forInjection, USP. The commercial formulations are diluted in 100 mL of0.9% sodium chloride before administration and the amount of thecommercial formulation used varies by patient and indication. Based onthe teachings described herein, a person of ordinary skill in the artcan determine formulations of Avastin™ to inject into therapeutic device100. In Europe, the Avastin™ formulation can be substantially similar tothe formulation of the United States.

For example, in the United States, there are 2 forms of Triamcinoloneused in injectable solutions, the acetonide and the hexacetonide. Theacetamide is approved for intravitreal injections in the U.S. Theacetamide is the active ingredient in TRIVARIS (Allergan), 8 mgtriamcinolone acetonide in 0.1 mL (8% suspension) in a vehiclecontaining w/w percents of 2.3% sodium hyaluronate; 0.63% sodiumchloride; 0.3% sodium phosphate, dibasic; 0.04% sodium phosphate,monobasic; and water, pH 7.0 to 7.4 for injection. The acetamide is alsothe active ingredient in Triesence™ (Alcon), a 40 mg/ml suspension.

A person of ordinary skill in the art can determine the osmolarity forthese formulations. The degree of dissociation of the active ingredientin solution can be determined and used to determined differences ofosmolarity from the molarity in these formulations. For example,considering at least some of the formulations may be concentrated (orsuspensions), the molarity can differ from the osmolarity.

The formulation of therapeutic agent may injected into therapeuticdevice 100 may comprise many known formulations of therapeutic agents,and the formulation therapeutic agent comprises an osmolatiry suitablefor release for an extended time from device 100. Table 1B showsexamples of osmolarity (Osm) of saline and some of the commerciallyformulations of Table 1A.

TABLE 1B Summary of Calculations Description Osm (M) Saline (0.9%) 0.308Phosphate Buffered Saline (PBS) 0.313 Lucentis ™ 0.289 Avastin ™ 0.182Triamcinolone Acetonide (Trivaris-Allergan) 0.342 TriamcinoloneAcetonide (Triessence - Alcon) Isotonic* Triamcinolone Acetonide(Kenalog - Apothecon) Isotonic* *As described in package insert

The vitreous humor of the eye comprises an osmolarity of about 290 mOsmto about 320 mOsm. Formulations of therapeutic agent having anosmolarity from about 280 mOsm to about 340 mOsm are substantiallyisotonic and substantially iso-osmotic with respect to the vitreoushumor of the eye. Although the formulations listed in Table 1B aresubstantially iso-osmotic and isotonic with respect to the vitreous ofthe eye and suitable for injection into the therapeutic device, theformulation of the therapeutic agent injected into the therapeuticdevice can be hypertonic (hyper-osmotic) or hypotonic (hypo-osmotic)with respect to the tonicity and osmolarity of the vitreous. Work inrelation to embodiments suggests that a hyper-osmotic formulation mayrelease the active ingredient of the therapeutic agent into the vitreoussomewhat faster initially when the solutes of the injected formulationequilibrate with the osmolatiry of the vitreous, and that a hypo-osmoticformulation such as Avastin™ may release the active ingredient of thetherapeutic agent into the vitreous somewhat slower initially when thesolutes of the injected formulation equilibrate with the eye. A personof ordinary skill in the art can conduct experiments based on theteaching described herein to determine empirically the appropriatereservoir chamber volume and porous structure for a formulation oftherapeutic agent disposed in the reservoir chamber, so as to releasetherapeutic amounts of the therapeutic agent for an extended time and toprovide therapeutic concentrations of therapeutic agent in the vitreouswithin a range of therapeutic concentrations that is above the minimuminhibitory concentration for the extended time.

FIG. 1D shows a therapeutic device 100 configured for placement in aneye as in FIGS. 1A-1 and 1A-1-1, in which the device comprises aplurality of chambers and channels connecting the chambers so as tolinearize the release of the therapeutic agent. A first chamber 132A maycomprise a reservoir having a first volume to contain the therapeuticquantity of the therapeutic agent. For example, the therapeutic agentcomprises the active ingredient contained within the reservoir. A secondchamber 132B can be disposed distally to the first chamber, with a firstopening connecting the first chamber and the second chamber. Thetherapeutic agent can diffuse through the first opening into the secondchamber. The second chamber comprises a second volume, such thattherapeutic agent is temporarily stored in the second chamber so as tolinearize, for example toward zero order, the delivery of thetherapeutic agent. A second opening can extend from the second chambertoward the vitreous humor. The first opening, the second opening and thesecond volume can be sized so as to linearize the delivery of thetherapeutic agent for the sustained release at therapeutic levels forthe extended time. More than one therapeutic agent can be inserted intothe therapeutic device. In such a case the two or more therapeuticagents may be mixed together or injected into separate chambers.

Additional chambers and openings can be disposed on the device tolinearize the delivery of the drug. For example, a third chamber can bedisposed distally to the second chamber. The second opening can couplethe second chamber to the third chamber. For example, a fourth chambercan be disposed distally to the third chamber, a third opening canconnect the third chamber and the fourth chamber.

Additionally or in the alternative, the therapeutic device may compriseat least one gate to provide for sustained drug delivery. The gate canbe moved from “closed” to “open” position using magnetism or by applyingelectrical current. For example the gates can slide or twist. The gatescan be spring-loaded, and may comprise a pump that can be re-loaded. Thegates may comprise an osmotic pump.

FIG. 1E shows a therapeutic device configured for placement in an eye asin FIGS. 1A-1 and 1A-1-1, in which the device comprises 100 needle stop170 located at the bottom of the therapeutic device. The needle stopthat may be included in the therapeutic device to keep the injectionneedle 189 from penetrating through and possibly damaging the exitport(s) 166 of the therapeutic device 100. The needle stop willdesirably be made of a material of sufficient rigidity to prevent theadvancement of the injection needle past a certain level in thetherapeutic device. Additionally or in the alternative, the length ofthe injector's needle may be designed so that it may not penetratethrough and possibly damage the exit port(s) of the therapeutic device.

As shown in FIGS. 1E and 1E-1, the needle stop 170 may be positioned atthe posterior end of the therapeutic device. FIGS. 1E-2, 1E-3 and 1E-3-1show other embodiments that may include needle stops placed in themiddle of the device. The needle stop may be designed in such a manneras to function as a flow diverter for the therapeutic agent. The shapeof the needle stop may encourage the mixing of the therapeutic agentwith the rest of the fluids present in the inner chamber(s) of thetherapeutic device.

FIG. 1E-1 shows a therapeutic device configured for placement in an eyeas in FIGS. 1A-1 and 1A-1-1, in which the device comprises needle stop170 located at the bottom of the therapeutic device and the shape of thedevice encourages the movement of the therapeutic agent within thechamber of the therapeutic device 100;

FIG. 1E-2 shows a therapeutic device configured for placement in an eyeas in FIGS. 1A-1 and 1A-1-1, in which the device comprises needle stop170 located in the middle of the therapeutic device;

FIG. 1E-3 shows a therapeutic device configured for placement in an eyeas in FIGS. 1A-1 and 1A-1-1, in which the device comprises needle stop170 located in the middle of the therapeutic device and the shape of thedevice encourages the movement of the therapeutic agent within thechamber of the therapeutic device;

FIG. 1E-3-1 shows a top view of the therapeutic device configured forplacement in an eye as in FIG. 1E-3;

FIG. 2 shows an access port 180 suitable for incorporation with thetherapeutic device 100. The access port 180 may be combined with thetherapeutic devices described herein, for example with reference toFIGS. 1A-1 to 1D. The access port may be disposed on a proximal end ofthe device. The access port 180 may comprise an opening formed in theretention structure 120 with a penetrable barrier 184 comprising aseptum 186 disposed thereon. The access port may 180 be configured forplacement under the conjunctiva 16 of the patient and above the sclera24.

FIG. 3A shows a collar 128 suitable for incorporation with thetherapeutic device 100. The retention structure 120 configured to coupleto the sclera 24 may comprise the collar 128. The collar may comprise anexpandable collar.

FIG. 3B shows biocompatible material impregnated with an anti-bacterialagent 310 on the therapeutic device 100 to inhibit bacterial growthalong the device from the sclera to the vitreous humor. Thebiocompatible material may comprise collagen, for example a collagensponge 312, and the anti-bacterial agent may comprise silver impregnatedin the collagen. The biocompatible material impregnated with thebactericide agent may extend around at least a portion of the outersurface of the device. The anti-bacterial agent may comprise a portionof the retention structure 120, such that the anti-bacterial agent isdisposed at least partially within the sclera when the device isinserted into the eye.

FIG. 4A shows released antibodies comprising antibody fragments 410 anda substrate 420 comprising binding agent 190, and FIG. 4B shows anantibody fragments 410 reversibly bound to a substrate 420 with bindingagent 190, in accordance with embodiments of the present invention. Theanti-body fragments can be reversibly bound to the substrate comprisingthe binding agent, such that the bound antibody fragments are inequilibrium with the unbound antibody fragments. One of ordinary skillin the art will recognize many substrates comprising binding agent toreversibly bind at least a portion of an antibody based on the teachingsdescribed herein. Examples of binding media may include particulatesused in chromatography, such as: Macro-Prep t-Butyl HIC Support,Macro-Prep DEAE Support, CHT Ceramic, Hydroxyapatite Type I, Macro-PrepCM Support, Macro-Prep Methyl HIC Support, Macro-Prep CeramicHydroxapatite Type II, UNOsphere S Cation Exchange Support, UNOsphere QStrong Anion Exchange Support, Macro-Prep High-S Support, and Macro-PrepHigh-Q Support. Additional media to test for binding include ionexchange and bioaffinity chromatography media based on a hydrophilicpolymeric support (GE Healthcare) that bind proteins with high capacity,and a hydrophilic packing material from Harvard Apparatus made frompoly(vinyl alcohol) that binds more protein than silica. Othercandidates would be known to those knowledgeable in the art.

FIG. 5A shows therapeutic device 100 coupled to injector 187 to inserttherapeutic agent 110 into container 130 of the device. The injector 187may comprise needle 189 coupled to a syringe 188.

FIG. 5A-1 shows a therapeutic device 100 coupled to an injector 187 toinject and remove material from the device. The injector may compriseneedle 189 having a first lumen 189A and a second lumen 189B configuredto insert into a container of the device. The injector maysimultaneously inject 510 therapeutic agent into and withdraw 520 liquidfrom the device. The injector may comprise a first one way valve and asecond one way valve coupled to the first lumen and the second lumen,respectively.

FIG. 5B shows a therapeutic device comprising a microloop channel 530.The microloop channel may extend to a first port 530A and a second port530B, such the therapeutic agent can be injected into the first port,for example with a binding agent, and flowable material, for exampleliquid comprising binding agent, can be drawn from the microloop channel530.

FIG. 5C-1 shows therapeutic device 100 comprising a tortuous channel540. The tortuous channel may comprise extend from a first port 540A toa second port 540B, such that the therapeutic agent can be injected intothe first port and flowable material, for example liquid comprising thebinding agent, can be drawn from the second channel.

FIG. 5C-2 shows a therapeutic device comprising a tortuous coiledchannel 550. The coiled channel 550 can extend to an exit port 552. Aneedle 189 can be inserted into the port 180 to inject therapeutic agentinto device 100.

FIG. 5D shows an expandable and contactible structure 562 to retain thetherapeutic agent and an outer rigid casing 560 to couple to the sclera.The expandable structure 562 may comprise a membrane, such as at leastone of a bag, a balloon, a flexible reservoir, a diaphragm, or a bag.The outer rigid casing may extend substantially around the structure 562and may comprise an opening to release liquid into the vitreous humorwhen the structure is expanded and to draw vitreous humor inside achamber of the casing when material is drawn from the structure and thestructure contacts.

FIGS. 5E shows a membrane 550 disposed over an exit port 552 oftherapeutic device 100.

FIG. 5F shows therapeutic device 100 comprising a tubular membrane 572clamped onto the therapeutic device over side ports 570 of device 100.

When the protective membranes have pores of 0.2 um diameter, they are 20or more times larger than the proteins of interest, which may comprise amodel for delivery of the therapeutic agent. For example, molecularweights and diameters of models of proteins of therapeutic interest are

(a) IgG 150 kDa  10.5 nm (b) BSA 69 kDa  7.2 nm (c) Fab fragment of IgG49 kDa hydrodynamic diameter not reported

Therefore, solutions of therapeutic compounds in the size range of IgGand BSA should flow relatively easily through 0.2 um pore sizeprotective membranes used to stop passage of bacterial and other cells.

Binding Materials/Agents may comprise at least one of a chemical bindingagent/material, a structural binding agent or material, or anelectrostatic binding agent or material. The types of binding agent maycomprise a classification composed of non-biodegradable material, forexample at glass beads, glass wool or a glass rod. A surface can bederivatized with at least one functional group so as to impart thebinding agent or material with the potential for at least one of ionic,hydrophobic, or bioaffinity binding to at least one therapeuticcompound.

The binding agent may comprise a biodegradable material. For example,the biodegradation, binding, or a combination of the previous processesmay control the diffusion rate.

The binding agent may comprise ion exchange, and the ion exchange maycomprise at least one of a functional group, a pH sensitive binding or apositive or negative charge. For example, ion exchange with at least oneof diethylaminoethyl or carboxymethyl functional groups.

The binding agent may comprise a pH sensitive binding agent. For examplethe binding agent can be configured to elute therapeutic agent at a pHof 7, and to bind the therapeutic agent at a pH from about 4 to about6.5. A cation exchange binding agent can be configured, for example,such that at a pH of 7, the net negative charge of the binding agentdecreases causing a decrease in binding of the positively charged drugand release of the therapeutic agent. A target buffer can be providedwith the binding agent to reversibly couple the binding agent to thetherapeutic agent. The rate of release can be controlled, for exampleslowed down, by using insolubility of the buffer in the vitreous.Alternatively or in combination the elution can be limited by using aporous membrane or a physical property such as a size of an opening.

The ion exchange may comprise positive or negative ion exchange.

The binding agent may comprise hydrophobic interaction. For example, thebinding agent may comprise at least one binding to hydrophobic pockets,for example at least one of methyl, ethyl, propyl, butyl, t-butyl orphenyl functional groups.

The binding agent may comprise affinity, for example at least one of amacromolecular affinity or a metal chelation affinity. Examples caninclude a hydroxyapatite, or chelated metal, for example zinc.Iminodiacetic acid can be chelated with zinc.

The binding agent may comprise at least one of the following functions:charging, recharging or elution. The charging may comprise a porousmaterial injected therein so as to release the active ingredient. Theporous matter may have an extremely large inert surface area, whichsurface area is available for binding. The recharging may compriseremoving carrier+therapeutic agent; and adding freshly “charged”carrier+therapeutic agent.

The elution may comprise a byproduct, for example unbound binding agentthat can be removed. For example, diffusion (plug flow) of vitreous tochange conditions, e.g. pH to reduce interaction of therapeuticagent+carriers.

Additionally or in the alternative, a sustained drug delivery system ofthe therapeutic agent may comprise drug delivery packets, e.g.microspheres, that are activated. The packets can be activated with atleast one of photochemical activation, thermal activation orbiodegradation.

The therapeutic device may comprise at least one structure configured toprovide safety precautions. The device may comprise at least onestructure to prevent at least one of macrophage or other immune cellwithin the reservoir body; bacterial penetration; or retinal detachment.

The therapeutic device may be configured for other applications in thebody. Other routes of administration of drugs may include at least oneof intraocular, oral, subcutaneous, intramuscular, intraperitoneal,intranasal, dermal, intrathecal, intravascular, intra articular,pericardial, intraluminal in organs and gut or the like.

Conditions that may be treated and/or prevented using the drug deliverydevice and method described herein may include at least one of thefollowing: hemophilia and other blood disorders, growth disorders,diabetes, leukemia, hepatitis, renal failure, HIV infection, hereditarydiseases such as cerebrosidase deficiency and adenosine deaminasedeficiency, hypertension, septic shock, autoimmune diseases such asmultiple sclerosis, Graves disease, systemic lupus erythematosus andrheumatoid arthritis, shock and wasting disorders, cystic fibrosis,lactose intolerance, Crohn's disease, inflammatory bowel disease,gastrointestinal or other cancers, degenerative diseases, trauma,multiple systemic conditions such as anemia, and ocular diseases suchas, for example, retinal detachment, proliferative retinopathy,proliferative diabetic retinopathy, degenerative disease, vasculardiseases, occlusions, infection caused by penetrating traumatic injury,endophthalmitis such as endogenous/systemic infection, post-operativeinfections, inflammations such as posterior uveitis, retinitis orchoroiditis and tumors such as neoplasms and retinoblastoma.

Examples of therapeutic agents 110 that may be delivered by thetherapeutic device 100 are described in Table 1A and may includeTriamcinolone acetonide, Bimatoprost (Lumigan), Ranibizumab (Lucentis™),Travoprost (Travatan, Alcon), Timolol (Timoptic, Merck), Levobunalol(Betagan, Allergan), Brimonidine (Alphagan, Allergan), Dorzolamide(Trusopt, Merck), Brinzolamide (Azopt, Alcon). Additional examples oftherapeutic agents that may be delivered by the therapeutic deviceinclude antibiotics such as tetracycline, chlortetracycline, bacitracin,neomycin, polymyxin, gramicidin, cephalexin, oxytetracycline,chloramphenicol kanamycin, rifampicin, ciprofloxacin, tobramycin,gentamycin, erythromycin and penicillin; antifungals such asamphotericin B and miconazole; anti-bacterials such as sulfonamides,sulfadiazine, sulfacetamide, sulfamethizole and sulfisoxazole,nitrofurazone and sodium propionate; antivirals such as idoxuridine,trifluorotymidine, acyclovir, ganciclovir and interferon;antiallergenics such as sodium cromoglycate, antazoline, methapyriline,chlorpheniramine, pyrilamine, cetirizine and prophenpyridamine;anti-inflammatories such as hydrocortisone, hydrocortisone acetate,dexamethasone, dexamethasone 21-phosphate, fluocinolone, medrysone,prednisolone, prednisolone 21-phosphate, prednisolone acetate,fluoromethalone, betamethasone, and triamcinolone; non-steroidalanti-inflammatories such as salicylate, indomethacin, ibuprofen,diclofenac, flurbiprofen and piroxicam; decongestants such asphenylephrine, naphazoline and tetrahydrozoline; miotics andanticholinesterases such as pilocarpine, salicylate, acetylcholinechloride, physostigmine, eserine, carbachol, diisopropylfluorophosphate, phospholine iodide and demecarium bromide; mydriaticssuch as atropine sulfate, cyclopentolate, homatropine, scopolamine,tropicamide, eucatropine and hydroxyamphetamine; sypathomimetics such asepinephrine; antineoplastics such as carmustine, cisplatin andfluorouracil; immunological drugs such as vaccines and immunestimulants; hormonal agents such as estrogens, estradiol,progestational, progesterone, insulin, calcitonin, parathyroid hormoneand peptide and vasopressin hypothalamus releasing factor; betaadrenergic blockers such as timolol maleate, levobunolol Hcl andbetaxolol Hcl; growth factors such as epidermal growth factor,fibroblast growth factor, platelet derived growth factor, transforminggrowth factor beta, somatotropin and fibronectin; carbonic anhydraseinhibitors such as dichlorophenamide, acetazolamide and methazolamideand other drugs such as prostaglandins, antiprostaglandins andprostaglandin precursors. Other therapeutic agents known to thoseskilled in the art which are capable of controlled, sustained releaseinto the eye in the manner described herein are also suitable for use inaccordance with embodiments of the present invention.

The therapeutic agent 110 may comprise one or more of the following:Abarelix, Abatacept, Abciximab, Adalimumab, Aldesleukin, Alefacept,Alemtuzumab, Alpha-1-proteinase inhibitor, Alteplase, Anakinra,Anistreplase, Antihemophilic Factor, Antithymocyte globulin, Aprotinin,Arcitumomab, Asparaginase, Basiliximab, Becaplermin, Bevacizumab,Bivalirudin, Botulinum Toxin Type A, Botulinum Toxin Type B, Capromab,Cetrorelix, Cetuximab, Choriogonadotropin alfa, Coagulation Factor IX,Coagulation factor VIIa, Collagenase, Corticotropin, Cosyntropin,Cyclosporine, Daclizumab, Darbepoetin alfa, Defibrotide, Denileukindiftitox, Desmopressin, Dornase Alfa,Drotrecogin alfa, Eculizumab,Efalizumab, Enfuvirtide, Epoetin alfa, Eptifibatide, Etanercept,Exenatide, Felypressin, Filgrastim, Follitropin beta, Galsulfase,Gemtuzumab ozogamicin, Glatiramer Acetate, Glucagon recombinant,Goserelin, Human Serum Albumin, Hyaluronidase, Ibritumomab, Idursulfase,Immune globulin, Infliximab, Insulin Glargine recombinant, InsulinLyspro recombinant, Insulin recombinant, Insulin, porcine, InterferonAlfa-2a, Recombinant, Interferon Alfa-2b, Recombinant, Interferonalfacon-1, Interferonalfa-n1, Interferon alfa-n3, Interferon beta-1b,Interferon gamma-1b, Lepirudin, Leuprolide, Lutropin alfa, Mecasermin,Menotropins, Muromonab, Natalizumab, Nesiritide, Octreotide, Omalizumab,Oprelvekin, OspA lipoprotein, Oxytocin, Palifermin, Palivizumab,Panitumumab, Pegademase bovine, Pegaptanib, Pegaspargase, Pegfilgrastim,Peginterferon alfa-2a, Peginterferon alfa-2b, Pegvisomant, Pramlintide,Ranibizumab, Rasburicase, Reteplase, Rituximab, Salmon Calcitonin,Sargramostim, Secretin, Sermorelin, Serum albumin iodonated, Somatropinrecombinant, Streptokinase, Tenecteplase, Teriparatide, ThyrotropinAlfa, Tositumomab, Trastuzumab, Urofollitropin, Urokinase, orVasopressin. The molecular weights of the molecules and indications ofthese therapeutic agents are set for below in Table 1A, below.

The therapeutic agent 110 may comprise one or more of compounds that actby binding members of the immunophilin family of cellular proteins. Suchcompounds are known as “immunophilin binding compounds.” Immunophilinbinding compounds include but are not limited to the “limus” family ofcompounds. Examples of limus compounds that may be used include but arenot limited to cyclophilins and FK506-binding proteins (FKBPs),including sirolimus (rapamycin) and its water soluble analog SDZ-RAD,tacrolimus, everolimus, pimecrolimus, CCI-779 (Wyeth), AP23841 (Ariad),and ABT-578 (Abbott Laboratories).

The limus family of compounds may be used in the compositions, devicesand methods for the treatment, prevention, inhibition, delaying theonset of, or causing the regression of angiogenesis-mediated diseasesand conditions of the eye, including choroidal neovascularization. Thelimus family of compounds may be used to prevent, treat, inhibit, delaythe onset of, or cause regression of AMD, including wet AMD. Rapamycinmay be used to prevent, treat, inhibit, delay the onset of, or causeregression of angiogenesis-mediated diseases and conditions of the eye,including choroidal neovascularization. Rapamycin may be used toprevent, treat, inhibit, delay the onset of, or cause regression of AMD,including wet AMD.

The therapeutic agent 110 may comprise one or more of: pyrrolidine,dithiocarbamate (NF.kappa.B inhibitor); squalamine; TPN 470 analogue andfumagillin; PKC (protein kinase C) inhibitors; Tie-1 and Tie-2 kinaseinhibitors; inhibitors of VEGF receptor kinase; proteosome inhibitorssuch as Velcade™ (bortezomib, for injection; ranibuzumab (Lucentis™) andother antibodies directed to the same target; pegaptanib (Macugen™);vitronectin receptor antagonists, such as cyclic peptide antagonists ofvitronectin receptor-type integrins; .alpha.-v/.beta.-3 integrinantagonists; .alpha.-v/.beta.-1 integrin antagonists; thiazolidinedionessuch as rosiglitazone or troglitazone; interferon, including.gamma.-interferon or interferon targeted to CNV by use of dextran andmetal coordination; pigment epithelium derived factor (PEDF);endostatin; angiostatin; tumistatin; canstatin; anecortave acetate;acetonide; triamcinolone; tetrathiomolybdate; RNA silencing or RNAinterference (RNAi) of angiogenic factors, including ribozymes thattarget VEGF expression; Accutane™ (13-cis retinoic acid); ACEinhibitors, including but not limited to quinopril, captopril, andperindozril; inhibitors of mTOR (mammalian target of rapamycin);3-aminothalidomide; pentoxifylline; 2-methoxyestradiol; colchicines;AMG-1470; cyclooxygenase inhibitors such as nepafenac, rofecoxib,diclofenac, rofecoxib, NS398, celecoxib, vioxx, and(E)-2-alkyl-2(4-methanesulfonylphenyl)-1-phenylethene; t-RNA synthasemodulator; metalloprotease 13 inhibitor; acetylcholinesterase inhibitor;potassium channel blockers; endorepellin; purine analog of6-thioguanine; cyclic peroxide ANO-2; (recombinant) arginine deiminase;epigallocatechin-3-gallate; cerivastatin; analogues of suramin; VEGFtrap molecules; apoptosis inhibiting agents; Visudyne™, snET2 and otherphoto sensitizers, which may be used with photodynamic therapy (PDT);inhibitors of hepatocyte growth factor (antibodies to the growth factoror its receptors, small molecular inhibitors of the c-met tyrosinekinase, truncated versions of HGF e.g. NK4).

The therapeutic agent 110 may comprise a combination with othertherapeutic agents and therapies, including but not limited to agentsand therapies useful for the treatment of angiogenesis orneovascularization, particularly CNV. Non-limiting examples of suchadditional agents and therapies include pyrrolidine, dithiocarbamate(NF.kappa.B inhibitor); squalamine; TPN 470 analogue and fumagillin; PKC(protein kinase C) inhibitors; Tie-1 and Tie-2 kinase inhibitors;inhibitors of VEGF receptor kinase; proteosome inhibitors such asVelcade™ (bortezomib, for injection; ranibuzumab (Lucentis™) and otherantibodies directed to the same target; pegaptanib (Macugen™);vitronectin receptor antagonists, such as cyclic peptide antagonists ofvitronectin receptor-type integrins; .alpha.-v/.beta.-3 integrinantagonists; .alpha.-v/.beta.-1 integrin antagonists; thiazolidinedionessuch as rosiglitazone or troglitazone; interferon, including.gamma.-interferon or interferon targeted to CNV by use of dextran andmetal coordination; pigment epithelium derived factor (PEDF);endostatin; angiostatin; tumistatin; canstatin; anecortave acetate;acetonide; triamcinolone; tetrathiomolybdate; RNA silencing or RNAinterference (RNAi) of angiogenic factors, including ribozymes thattarget VEGF expression; Accutane™ (13-cis retinoic acid); ACEinhibitors, including but not limited to quinopril, captopril, andperindozril; inhibitors of mTOR (mammalian target of rapamycin);3-aminothalidomide; pentoxifylline; 2-methoxyestradiol; colchicines;AMG-1470; cyclooxygenase inhibitors such as nepafenac, rofecoxib,diclofenac, rofecoxib, NS398, celecoxib, vioxx, and(E)-2-alkyl-2(4-methanesulfonylphenyl)-1-phenylethene; t-RNA synthasemodulator; metalloprotease 13 inhibitor; acetylcholinesterase inhibitor;potassium channel blockers; endorepellin; purine analog of6-thioguanine; cyclic peroxide ANO-2; (recombinant) arginine deiminase;epigallocatechin-3-gallate; cerivastatin; analogues of suramin; VEGFtrap molecules; inhibitors of hepatocyte growth factor (antibodies tothe growth factor or its receptors, small molecular inhibitors of thec-met tyrosine kinase, truncated versions of HGF e.g. NK4); apoptosisinhibiting agents; Visudyne™, snET2 and other photo sensitizers withphotodynamic therapy (PDT); and laser photocoagulation.

The therapeutic agents may be used in conjunction with apharmaceutically acceptable carrier such as, for example, solids such asstarch, gelatin, sugars, natural gums such as acacia, sodium alginateand carboxymethyl cellulose; polymers such as silicone rubber; liquidssuch as sterile water, saline, dextrose, dextrose in water or saline;condensation products of castor oil and ethylene oxide, liquid glyceryltriester of a lower molecular weight fatty acid; lower alkanols; oilssuch as corn oil, peanut oil, sesame oil, castor oil, and the like, withemulsifiers such as mono- or di-glyceride of a fatty acid, or aphosphatide such as lecithin, polysorbate 80, and the like; glycols andpolyalkylene glycols; aqueous media in the presence of a suspendingagent, for example, sodium carboxymethylcellulose, sodium hyaluronate,sodium alginate, poly(vinyl pyrrolidone) and similar compounds, eitheralone, or with suitable dispensing agents such as lecithin,polyoxyethylene stearate and the like. The carrier may also containadjuvants such as preserving, stabilizing, wetting, emulsifying agentsor other related materials.

The therapeutic device may comprise a container configured to hold atleast one therapeutic agent, the container comprising a chamber to holdthe at least one therapeutic agent with at least one opening to releasethe at least one therapeutic agent to the vitreous humor and porousstructure 150 placed within the at least one opening. The porousstructure 150 may comprise a fixed tortuous, porous material such as asintered metal, a sintered glass or a sintered polymer with a definedporosity and tortuosity that controls the rate of delivery of the atleast one therapeutic agent to the vitreous humor. The rigid porousstructures provide certain advantages over capillary tubes, erodiblepolymers and membranes as a mechanism for controlling the release of atherapeutic agent or agents from the therapeutic device. Theseadvantages include the ability of the rigid porous structure to comprisea needle stop, simpler and more cost effective manufacture, flushabilityfor cleaning or declogging either prior to or after implantation, highefficiency depth filtration of microorganisms provided by the labyrinthsof irregular paths within the structure and greater robustness due togreater hardness and thickness of the structure compared to a membraneor erodible polymer matrix. Additionally, when the rigid porousstructure is manufactured from a sintered metal, ceramic, glass orcertain plastics, it can be subjected to sterilization and cleaningprocedures, such as heat or radiation based sterilization anddepyrogenation, that might damage polymer and other membranes. Incertain embodiments, as illustrated in example 9, the rigid porousstructure may be configured to provide a therapeutically effective,concentration of the therapeutic agent in the vitreous for at least 6months. This release profile provided by certain configurations of therigid porous structures enables a smaller device which is preferred in asmall organ such as the eye where larger devices may alter or impairvision.

FIG. 6A1 shows a therapeutic device 100 comprising a container 130having a penetrable barrier 184 disposed on a first end, a porousstructure 150 disposed on a second end to release therapeutic agent foran extended period, and a retention structure 120 comprising anextension protruding outward from the container to couple to the scleraand the conjunctiva. The extending protrusion of the retention structuremay comprise a diameter 120D. The retention structure may comprise anindentation 120I sized to receive the sclera. The container may comprisea tubular barrier 160 that defines at least a portion of the reservoir,and the container may comprise a width, for example a diameter 134. Thediameter 134 can be sized within a range, for example within a rangefrom about 0.5 to about 4 mm, for example within a range from about 1 to3 mm and can be about 2 mm, for example. The container may comprise alength 136, sized so as to extend from the conjunctive to the vitreousto release the therapeutic agent into the vitreous. The length 136 canbe sized within a range, for example within a range from about 2 toabout 1 4 mm, for example within a range from about 4 to 10 mm and canbe about 7 mm, for example. The volume of the reservoir may besubstantially determined by an inner cross sectional area of the tubularstructure and distance from the porous structure to the penetrablebarrier. The retention structure may comprise an annular extensionhaving a retention structure diameter greater than a diameter of thecontainer. The retention structure may comprise an indentationconfigured to receive the sclera when the extension extends between thesclera and the conjunctive. The penetrable barrier may comprise a septumdisposed on a proximal end of the container, in which the septumcomprises a barrier that can be penetrated with a sharp object such as aneedle for injection of the therapeutic agent. The porous structure maycomprise a cross sectional area 150A sized to release the therapeuticagent for the extended period.

The porous structure 150 may comprise a first side coupled to thereservoir 150 S1 and a second side to couple to the vitreous 150S2. Thefirst side may comprise a first area 150A1 and the second side maycomprise a second area 150A2. The porous structure may comprise athickness 105T. The porous structure many comprise a diameter 150D.

The volume of the reservoir 140 may comprise from about 5 uL to about2000 uL of therapeutic agent, or for example from about 10 uL to about200 uL of therapeutic agent.

The therapeutic agent stored in the reservoir of the container comprisesat least one of a solid comprising the therapeutic agent, a solutioncomprising the therapeutic agent, a suspension comprising thetherapeutic agent, particles comprising the therapeutic agent adsorbedthereon, or particles reversibly bound to the therapeutic agent. Forexample, reservoir may comprise a suspension of a cortico-steroid suchas triamcinolone acetonide to treat inflammation of the retina. Thereservoir may comprise a buffer and a suspension of a therapeutic agentcomprising solubility within a range from about 1 ug/mL to about 100ug/mL, such as from about 1 ug/mL to about 40 ug/mL. For example, thetherapeutic agent may comprise a suspension of triamcinolone acetonidehaving a solubility of approximately 19 ug/mL in the buffer at 37 C whenimplanted.

The release rate index may comprise many values, and the release rateindex with the suspension may be somewhat higher than for a solution inmany embodiments, for example. The release rate index may be no morethan about 5, and can be no more than about 2.0, for example no morethan about 1.5, and in many embodiments may be no more than about 1.2,so as to release the therapeutic agent with therapeutic amounts for theextended time.

The therapeutic device, including for example, the retention structureand the porous structure, may be sized to pass through a lumen of acatheter.

The porous structure may comprise a needle stop that limits penetrationof the needle. The porous structure may comprise a plurality of channelsconfigured for the extended release of the therapeutic agent. The porousstructure may comprise a rigid sintered material having characteristicssuitable for the sustained release of the material.

FIG. 6A2 shows a therapeutic device as in FIG. 6A comprising a roundeddistal end.

FIG. 6B shows a rigid porous structure as in FIG. 6A. The rigid porousstructure 158 comprises a plurality of interconnecting channels 156. Theporous structure comprises a sintered material composed ofinterconnected grains 155 of material. The interconnected grains ofmaterial define channels that extend through the porous material torelease the therapeutic agent. The channels may extend around thesintered grains of material, such that the channels compriseinterconnecting channels extending through the porous material.

The rigid porous structure can be configured for injection of thetherapeutic agent into the container in many ways. The channels of therigid porous structure may comprise substantially fixed channels whenthe therapeutic agent is injected into the reservoir with pressure. Therigid porous structure comprises a hardness parameter within a rangefrom about 160 Vickers to about 500 Vickers. In some embodiments therigid porous structure is formed from sintered stainless steel andcomprises a hardness parameter within a range from about 200 Vickers toabout 240 Vickers. In some embodiments it is preferred to inhibitejection of the therapeutic agent through the porous structure duringfilling or refilling the reservoir of the therapeutic device with afluid. In these embodiments the channels of the rigid porous structurecomprise a resistance to flow of an injected solution or suspensionthrough a thirty gauge needle such that ejection of said solution orsuspension through the rigid porous structure is substantially inhibitedwhen said solution or suspension is injected into the reservoir of thetherapeutic device. Additionally, these embodiments may optionallycomprise an evacuation vent or an evacuation reservoir under vacuum orboth to facilitate filling or refilling of the reservoir.

The reservoir and the porous structure can be configured to releasetherapeutic amounts of the therapeutic agent in many ways. The reservoirand the porous structure can be configured to release therapeuticamounts of the therapeutic agent corresponding to a concentration of atleast about 0.1 ug per ml of vitreous humor for an extended period of atleast about three months. The reservoir and the porous structure can beconfigured to release therapeutic amounts of the therapeutic agentcorresponding to a concentration of at least about 0.1 ug per ml ofvitreous humor and no more than about 10 ug per ml for an extendedperiod of at least about three months. The therapeutic agent maycomprise at least a fragment of an antibody and a molecular weight of atleast about 10 k Daltons. For example, the therapeutic agent maycomprise one or more of ranibizumab or bevacizumab. Alternatively or incombination, the therapeutic agent may comprise a small molecule drugsuitable for sustained release. The reservoir and the porous structuremay be configured to release therapeutic amounts of the therapeuticagent corresponding to a concentration of at least about 0.1 ug per mlof vitreous humor and no more than about 10 ug per ml for an extendedperiod of at least about 3 months or at least about 6 months. Thereservoir and the porous structure can be configured to releasetherapeutic amounts of the therapeutic agent corresponding to aconcentration of at least about 0.1 ug per ml of vitreous humor and nomore than about 10 ug per ml for an extended period of at least abouttwelve months or at least about two years or at least about three years.The reservoir and the porous structure may also be configured to releasetherapeutic amounts of the therapeutic agent corresponding to aconcentration of at least about 0.01 ug per ml of vitreous humor and nomore than about 300 ug per ml for an extended period of at least about 3months or 6 months or 12 months or 24 months.

The channels of the rigid porous structure comprise a hydrogelconfigured to limit a size of molecules passed through the channels ofthe rigid porous structure. For example, the hydrogel can be formedwithin the channels and may comprise an acrylamide gel. The hydrogelcomprises a water content of at least about 70%. For example, thehydrogel may comprise a water content of no more than about 90% to limitmolecular weight of the therapeutic agent to about 30 k Daltons. Thehydrogel comprises a water content of no more than about 95% to limitmolecular weight of the therapeutic agent to about 100 k Daltons. Thehydrogel may comprise a water content within a range from about 90% toabout 95% such that the channels of the porous material are configuredto pass Lucentis™ and substantially not pass Avastin™.

The rigid porous structure may comprise a composite porous material thatcan readily be formed in or into a wide range of different shapes andconfigurations. For example, the porous material can be a composite of ametal, aerogel or ceramic foam (i.e., a reticulated intercellularstructure in which the interior cells are interconnected to provide amultiplicity of pores passing through the volume of the structure, thewalls of the cells themselves being substantially continuous andnon-porous, and the volume of the cells relative to that of the materialforming the cell walls being such that the overall density of theintercellular structure is less than about 30 percent theoreticaldensity) the through pores of which are impregnated with a sinteredpowder or aerogel. The thickness, density, porosity and porouscharacteristics of the final composite porous material can be varied toconform with the desired release of the therapeutic agent.

Embodiments comprise a method of making an integral (i.e.,single-component) porous structure. The method may comprise introducingparticles into a mold having a desired shape for the porous structure.The shape includes a proximal end defining a plurality of proximalporous channel openings to couple to the reservoir, a distal enddefining a plurality of outlet channel openings to couple to thevitreous humor of the eye, a plurality of blind inlet cavities extendinginto the filter from the proximal openings, and a plurality of blindoutlet cavities extending into the porous structure from the outletchannel openings. The method further includes applying pressure to themold, thereby causing the particles to cohere and form a singlecomponent, and sintering the component to form the porous structure. Theparticles can be pressed and cohere to form the component without theuse of a polymeric binder, and the porous structure can be formedsubstantially without machining.

The mold can be oriented vertically with the open other end disposedupwardly, and metal powder having a particle size of less than 20micrometers can be introduced into the cavity through the open end ofthe mold while vibrating the mold to achieve substantially uniformpacking of the metal powder in the cavity. A cap can be placed on theopen other end of the mold, and pressure is applied to the mold andthereby to the metal powder in the cavity to cause the metal powder tocohere and form a cup-shaped powdered metal structure having a shapecorresponding to the mold. The shaped powdered metal structure can beremoved from the mold, and sintered to obtain a porous sintered metalporous structure.

The metal porous structure can be incorporated into the device by apress fit into an impermeable structure with an opening configured toprovide a tight fit with the porous structure. Other means, such aswelding, known to those skilled in the art can be used to incorporatethe porous structure into the device. Alternatively, or in combination,the powdered metal structure can be formed in a mold where a portion ofthe mold remains with the shaped powdered metal structure and becomespart of the device. This may be advantageous in achieving a good sealbetween the porous structure and the device.

The release rate of therapeutic agent through a porous body, such as asintered porous metal structure or a porous glass structure, may bedescribed by diffusion of the of the therapeutic agent within the porousstructure with the channel parameter, and with an effective diffusioncoefficient equal to the diffusion coefficient of the therapeutic agentin the liquid that fills the reservoir multiplied by the Porosity and aChannel Parameter of the porous body:Release Rate=(D P/F) A (c _(R) −c _(v))/L, where:

-   c_(R)=Concentration in reservoir-   c_(v)=Concentration outside of the reservoir or in the vitreous-   D=Diffusion coefficient of the therapeutic agent in the reservoir    solution-   P=Porosity of porous structure-   F=Channel parameter that may correspond to a tortuosity parameter of    channels of porous structure-   A=Area of porous structure-   L=Thickness (length) of porous structure    Cumulative Release=1−cR/cR0=1−exp((−D PA/FL V _(R))t), where-   t=time, Vr=reservoir volume

The release rate index can (hereinafter RRI) be used to determinerelease of the therapeutic agent. The RRI may be defined as (PA/FL), andthe RRI values herein will have units of mm unless otherwise indicated.Many of the porous structures used in the therapeutic delivery devicesdescribed here have an RRI of no more than about 5.0, often no more thanabout 2.0, and can be no more than about 1.2 mm.

The channel parameter can correspond to an elongation of the path of thetherapeutic agent released through the porous structure. The porousstructure may comprise many interconnecting channels, and the channelparameter can correspond to an effective length that the therapeuticagent travels along the interconnecting channels of the porous structurefrom the reservoir side to the vitreous side when released. The channelparameter multiplied by the thickness (length) of the porous structurecan determine the effective length that the therapeutic agent travelsalong the interconnecting channels from the reservoir side to thevitreous side. For example, the channel parameter (F) of about 1.5corresponds to interconnecting channels that provide an effectiveincrease in length traveled by the therapeutic agent of about 50%, andfor a 1 mm thick porous structure the effective length that thetherapeutic agent travels along the interconnecting channels from thereservoir side to the vitreous side corresponds to about 1.5 mm. Thechannel parameter (F) of at least about 2 corresponds to interconnectingchannels that provide an effective increase in length traveled by thetherapeutic agent of about 100%, and for a 1 mm thick porous structurethe effective length that the therapeutic agent travels along theinterconnecting channels from the reservoir side to the vitreous sidecorresponds to at least about 2.0 mm. As the porous structure comprisesmany interconnecting channels that provide many alternative paths forrelease of the therapeutic agent, blockage of some of the channelsprovides no substantial change in the effective path length through theporous structure as the alternative interconnecting channels areavailable, such that the rate of diffusion through the porous structureand the release of the therapeutic agent are substantially maintainedwhen some of the channels are blocked.

If the reservoir solution is aqueous or has a viscosity similar towater, the value for the diffusion coefficient of the therapeutic agent(TA) in water at the temperature of interest may be used. The followingequation can be used to estimate the diffusion coefficient at 37° C.from the measured value of D_(BSA,20C)=6.1 e-7 cm2/s for bovine serumalbumin in water at 20° C. (Molokhia et al, Exp Eye Res 2008):D _(TA, 37C) =D _(BSA,20C)(η_(20C)/η_(37C))(MW _(BSA)/MW _(TA))^(1/3)whereMW refers to the molecular weight of either BSA or the test compound andη is the viscosity of water. The following lists diffusion coefficientsof proteins of interest.

Diff Coeff Compound MW Temp C. (cm{circumflex over ( )}2/s) BSA 69,00020 6.1E−07 BSA 69,000 37 9.1E−07 Ranibizumab 48,000 20 6.9E−07Ranibizumab 48,000 37 1.0E−06 Bevacizumab 149,000 20 4.7E−07 Bevacizumab149,000 37 7.1E−07Small molecules have a diffusion coefficient similar to fluorescein(MW=330, D=4.8 to 6 e-6 cm²/s from Stay, M S et al. Pharm Res 2003,20(1), pp. 96-102). For example, the small molecule may comprise aglucocorticoid such as triamcinolone acetonide having a molecular weightof about 435.

The porous structure comprises a porosity, a thickness, a channelparameter and a surface area configured to release therapeutic amountsfor the extended period. The porous material may comprise a porositycorresponding to the fraction of void space of the channels extendingwithin the material. The porosity comprises a value within a range fromabout 3% to about 70%. In other embodiments, the porosity comprises avalue with a range from about 5% to about 10% or from about 10% to about25%, or for example from about 15% to about 20%. Porosity can bedetermined from the weight and macroscopic volume or can be measured vianitrogen gas adsorption

The porous structure may comprise a plurality of porous structures, andthe area used in the above equation may comprise the combined area ofthe plurality of porous structures.

The channel parameter may comprise a fit parameter corresponding to thetortuosity of the channels. For a known porosity, surface area andthickness of the surface parameter, the curve fit parameter F, which maycorrespond to tortuosity of the channels can be determined based onexperimental measurements. The parameter PA/FL can be used to determinethe desired sustained release profile, and the values of P, A, F and Ldetermined. The rate of release of the therapeutic agent corresponds toa ratio of the porosity to the channel parameter, and the ratio of theporosity to the channel parameter can be less than about 0.5 such thatthe porous structure releases the therapeutic agent for the extendedperiod. For example, the ratio of the porosity to the channel parameteris less than about 0.1 or for example less than about 0.2 such that theporous structure releases the therapeutic agent for the extended period.The channel parameter may comprise a value of at least about 1, such asat least about 1.2. For example, the value of the channel parameter maycomprise at least about 1.5, for example at least about 2, and maycomprise at least about 5. The channel parameter can be within a rangefrom about 1.1 to about 10, for example within a range from about 1.2 toabout 5. A person of ordinary skill in the art can conduct experimentsbased on the teachings described herein to determine empirically thechannel parameter to release the therapeutic agent for an intendedrelease rate profile.

The area in the model originates from the description of masstransported in units of flux; i.e., rate of mass transfer per unit area.For simple geometries, such as a porous disc mounted in an impermeablesleeve of equal thickness, the area corresponds to one face of the discand the thickness, L, is the thickness of the disc. For more complexgeometries, such as a porous body in the shape of a truncated cone, theeffective area is a value in between the area where therapeutic agententers the porous body and the area where therapeutic agent exits theporous body.

A model can be derived to describe the release rate as a function oftime by relating the change of concentration in the reservoir to therelease rate described above. This model assumes a solution oftherapeutic agent where the concentration in the reservoir is uniform.In addition, the concentration in the receiving fluid or vitreous isconsidered negligible (c_(v)=0). Solving the differential equation andrearrangement yields the following equations describing theconcentration in the reservoir as a function of time, t, and volume ofthe reservoir, V_(R), for release of a therapeutic agent from a solutionin a reservoir though a porous structure.c _(R) =c _(R0) exp ((−D PA/FL V _(R)) t)and Cumulative Release=1−c_(R)/c_(R0)

When the reservoir contains a suspension, the concentration inreservoir, c_(R), is the dissolved concentration in equilibrium with thesolid (i.e., the solubility of the therapeutic agent). In this case, theconcentration in the reservoir is constant with time, the release rateis zero order, and the cumulative release increases linearly with timeuntil the time when the solid is exhausted.

Therapeutic concentrations for many ophthalmic therapeutic agents may bedetermined experimentally by measuring concentrations in the vitreoushumor that elicit a therapeutic effect. Therefore, there is value inextending predictions of release rates to predictions of concentrationsin the vitreous. A one-compartment model may be used to describeelimination of therapeutic agent from eye tissue.

Current intravitreal administration of therapeutic agents such asLucentis™ involves a bolus injection. A bolus injection into thevitreous may be modeled as a single exponential with rate constant,k=0.693/half-life and a cmax=dose/V_(v) where V_(v) is the vitreousvolume. As an example, the half-life for ranibizumab is approximately 3days in the rabbit and the monkey (Gaudreault et al) and 9 days inhumans (Lucentis™ package insert). The vitreous volume is approximately1.5 mL for the rabbit and monkey and 4.5 mL for the human eye. The modelpredicts an initial concentration of 333 ug/mL for a bolus injection of0.5 mg Lucentis™ into the eye of a monkey. This concentration decays toa vitreous concentration of 0.1 ug/mL after about a month.

For devices with extended release, the concentration in the vitreouschanges slowly with time. In this situation, a model can be derived froma mass balance equating the release rate from the device (described byequations above) with the elimination rate from the eye, k c_(v) V_(v).Rearrangement yields the following equation for the concentration in thevitreous:c _(v)=Release rate from device/k V _(v).

Since the release rate from a device with a solution of therapeuticagent decreases exponentially with time, the concentration in thevitreous decreases exponentially with the same rate constant. In otherwords, vitreous concentration decreases with a rate constant equal to DPA/FL V_(R) and, hence, is dependent on the properties of the porousstructure and the volume of the reservoir.

Since the release rate is zero order from a device with a suspension oftherapeutic agent, the vitreous concentration will also betime-independent. The release rate will depend on the properties of theporous structure via the ratio, PA/FL, but will be independent of thevolume of the reservoir until the time at which the drug is exhausted.

The channels of the rigid porous structure can be sized in many ways torelease the intended therapeutic agent. For example, the channels of therigid porous structure can be sized to pass therapeutic agent comprisingmolecules having a molecular weight of at least about 100 Daltons or forexample, at least about 50 k Daltons. The channels of the rigid porousstructure can be sized to pass therapeutic agent comprising moleculescomprising a cross-sectional size of no more than about 10 nm. Thechannels of the rigid porous structure comprise interconnecting channelsconfigured to pass the therapeutic agent among the interconnectingchannels. The rigid porous structure comprises grains of rigid materialand wherein the interconnecting channels extend at least partiallyaround the grains of rigid material to pass the therapeutic agentthrough the porous material. The grains of rigid material can be coupledtogether at a loci of attachment and wherein the interconnectingchannels extend at least partially around the loci of attachment.

The porous structure and reservoir may be configured to release theglucocorticoid for an extended time of at least about six months with atherapeutic amount of glucocorticoid of corresponding to an in situconcentration within a range from about 0.05 ug/mL to about 4 ug/mL, forexample from 0.1 ug/mL to about 4 ug/mL, so as to suppress inflammationin the retina-choroid.

The porous structure comprises a sintered material. The sinteredmaterial may comprise grains of material in which the grains comprise anaverage size of no more than about 20 um. For example, the sinteredmaterial may comprise grains of material in which the grains comprise anaverage size of no more than about 10 um, an average size of no morethan about 5 um, or an average size of no more than about 1 um. Thechannels are sized to pass therapeutic quantities of the therapeuticagent through the sintered material for the extended time based on thegrain size of the sintered material and processing parameters such ascompaction force and time and temperature in the furnace. The channelscan be sized to inhibit penetration of microbes including bacteria andfungal spores through the sintered material.

The sintered material comprises a wettable material to inhibit bubbleswithin the channels of the material.

The sintered material comprises at least one of a metal, a ceramic, aglass or a plastic. The sintered material may comprises a sinteredcomposite material, and the composite material comprises two or more ofthe metal, the ceramic, the glass or the plastic. The metal comprises atleast one of Ni, Ti, nitinol, stainless steel including alloys such as304, 304L, 316 or 316L, cobalt chrome, elgiloy, hastealloy, c-276 alloyor Nickel 200 alloy. The sintered material may comprise a ceramic. Thesintered material may comprise a glass. The plastic may comprise awettable coating to inhibit bubble formation in the channels, and theplastic may comprise at least one of polyether ether ketone (PEEK),polyethylene, polypropylene, polyimide, polystyrene, polycarbonate,polyacrylate, polymethacrylate, or polyamide.

The rigid porous structure may comprise a plurality of rigid porousstructures coupled to the reservoir and configured to release thetherapeutic agent for the extended period. For example, additional rigidporous structure can be disposed along the container, for example theend of the container may comprise the porous structure, and anadditional porous structure can be disposed along a distal portion ofthe container, for example along a tubular sidewall of the container.

The therapeutic device can be tuned to release therapeutic amounts ofthe therapeutic agent above the minimum inhibitory concentration for anextended time based on bolus injections of the therapeutic agent. Forexample, the volume of the chamber of the reservoir can be sized withthe release rate of the porous structure based on the volume of thebolus injection. A formulation of a therapeutic agent can be provided,for example a known intravitreal injection formulation. The therapeuticagent can be capable of treating the eye with bolus injections, suchthat the formulation has a corresponding period between each of thebolus injections to treat the eye. For example the bolus injections maycomprise monthly injections. Each of the bolus injections comprises avolume of the formulation, for example 50 uL. Each of the bolusinjections of the therapeutic agent may correspond to a range oftherapeutic concentrations of the therapeutic agent within the vitreoushumor over the time course between injections, and the device can betuned so as to release therapeutic amounts of the therapeutic agent suchthat the vitreous concentrations of the released therapeutic agent fromthe device are within the range of therapeutic concentrations of thecorresponding bolus injections. For example, the therapeutic agent maycomprise a minimum inhibitory concentration to treat the eye, forexample at least about 3 ug/mL, and the values of the range oftherapeutic concentrations can be at least about 3 ug/mL. Thetherapeutic device can be configured to treat the eye with an injectionof the monthly volume of the formulation into the device, for examplethrough the penetrable barrier. The reservoir of the container has achamber to contain a volume of the therapeutic agent, for example 35 uL,and a mechanism to release the therapeutic agent from the chamber to thevitreous humor.

The volume of the container and the release mechanism can be tuned totreat the eye with the therapeutic agent with vitreous concentrationswithin the therapeutic range for an extended time with each injection ofthe quantity corresponding to the bolus injection, such that theconcentration of the therapeutic agent within the vitreous humor remainswithin the range of therapeutic concentrations and comprises at leastthe minimum inhibitory concentration. The extended time may comprise atleast about twice the corresponding period of the bolus injections. Therelease mechanism comprises one or more of a porous frit, a sinteredporous frit, a permeable membrane, a semi-permeable membrane, acapillary tube or a tortuous channel, nano-structures, nano-channels orsintered nano-particles. For example, the porous frit may comprises aporosity, cross sectional area, and a thickness to release thetherapeutic agent for the extended time. The volume of the containerreservoir can be sized in many ways in relation to the volume of theinjected formulation and can be larger than the volume of injectedformulation, smaller than the volume of injected formulation, orsubstantially the same as the volume of injected formulation. Forexample, the volume of the container may comprise no more than thevolume of the formulation, such that at least a portion of theformulation injected into the reservoir passes through the reservoir andcomprises a bolus injection to treat the patient immediately. As thevolume of the reservoir is increased, the amount of formulation releasedto the eye through the porous structure upon injection can decreasealong with the concentration of active ingredient of the therapeuticagent within the reservoir, and the release rate index can be increasedappropriately so as to provide thereapeutic amounts of therapeutic agentfor the extended time. For example, the volume of the reservoir of thecontainer can be greater than the volume corresponding to the bolusinjection, so as to provide therapeutic amounts for at least about fivemonths, for example 6 months, with an injection volume corresponding toa monthly injection of Lucentis™. For example, the formulation maycomprise commercially available Lucentis™, 50 uL, and the reservoir maycomprise a volume of about 100 uL and provide therapeutic vitreousconcentrations of at least about 3 ug/mL for six months with 50 uL ofLucentis™ injected into the reservoir.

The chamber may comprise a substantially fixed volume and the releaserate mechanism comprises a substantially rigid structure to maintainrelease of the therapeutic agent above the minimum inhibitoryconcentration for the extended time with each injection of a pluralityof injections.

A first portion of the injection may pass through the release mechanismand treat the patient when the formulation is injected, and a secondportion of the formulation can be contained in the chamber when theformulation is injected.

FIG. 6B-1 shows interconnecting channels 156 extending from first side150S1 to second side 150S2 of the porous structure as in FIG. 6B. Theinterconnecting channels 156 extend to a first opening 158A1, a secondopening 158A2 and an Nth opening 158AN on the first side 150S1. Theinterconnecting channels 156 extend to a first opening 158B1, a secondopening 158B2 and an Nth opening 158BN on the second side 150S2. Each ofthe openings of the plurality of channels on the first side is connectedto each of the openings of plurality of channels on the second side,such that effective length traveled along the channels is greater thanthickness 150T. The channel parameter can be within a range from about1.1 to about 10, such that the effective length is within a range fromabout 1.1 to 10 times the thickness 150T. For example, the channelparameter can be about 1 and the porosity about 0.2, such that theeffective length corresponds to at least about 5 times the thickness150T.

FIG. 6B-2 shows a plurality of paths of the therapeutic agent along theinterconnecting channels extending from a first side 150S1 to a secondside 150S2 of the porous structure as in FIGS. 6B and 6B-1. Theplurality of paths comprises a first path 156P1 extending from the firstside to the second side, a second path 156P2 extending from the firstside to the second side and a third path 156P3 extending from the firstside to the second side, and many additional paths. The effect length ofeach of first path P1, second path P2 and third path P3 is substantiallysimilar, such that each opening on the first side can release thetherapeutic agent to each interconnected opening on the second side. Thesubstantially similar path length can be related to the sintered grainsof material and the channels that extend around the sintered material.The porous structure may comprise randomly oriented and connected grainsof material, packed beads of material, or combinations thereof. Thechannel parameter can be related to the structure of the sintered grainsof material and corresponding interconnecting channels, porosity of thematerial, and percolation threshold. Work in relation to embodimentsshows that the percolation threshold of the sintered grains may be belowthe porosity of the porous frit structure, such that the channels arehighly inter-connected. The sintered grains of material can provideinterconnected channels, and the grains can be selected to providedesired porosity and channel parameters and RRI as described herein.

The channel parameter and effective length from the first side to thesecond side can be configured in many ways. The channel parameter can begreater than 1 and within a range from about 1.2 to about 5.0, such thatthe effective length is within a range about 1.2 to 5.0 times thethickness 150T, although the channel parameter may be greater than 5,for example within a range from about 1.2 to 10. For example, thechannel parameter can be from about 1.3 to about 2.0, such that theeffective length is about 1.3 to 2.0 times the thickness 150T. Forexample, experimental testing has shown the channel parameter can befrom about 1.4 to about 1.8, such that the effective length is about 1.4to 1.8 times the thickness 150T, for example about 1.6 times thethickness. These values correspond to the paths of the channels aroundthe sintered grains of material, and may correspond, for example, to thepaths of channels around packed beads of material.

FIG. 6B-3 shows blockage of the openings with a covering 156B and theplurality of paths of the therapeutic agent along the interconnectingchannels extending from a first side to a second side of the porousstructure as in FIGS. 6B and 6B-1. A plurality of paths 156PR extendfrom the first side to the second side couple the first side to thesecond side where one of the sides is covered, such that the flow rateis maintained when one of the sides is partially covered.

FIG. 6B-4 shows blockage of the openings with particles 156PB and theplurality of paths of the therapeutic agent along the interconnectingchannels extending from a first side to a second side of the porousstructure as in FIGS. 6B and 6B-1. The plurality of paths 156PR extendfrom the first side to the second side couple the first side to thesecond side where one of the sides is covered, such that the flow rateis maintained when one of the sides is partially covered

FIG. 6B-5 shows an effective cross-sectional size 150DE and area 150EFFcorresponding to the plurality of paths of the therapeutic agent alongthe interconnecting channels extending from a first side to a secondside of the porous structure as in FIGS. 6B and 6B-1. The effectivecross sectional area of the interconnecting channels corresponds to theinternal cross-sectional area of the porous structure disposed betweenthe openings of the first side and the openings of the second side, suchthat the rate of release can be substantially maintained when thechannels are blocked on the first side and the second side.

The rigid porous structure can be shaped and molded in many ways forexample with tubular shapes, conical shapes, discs and hemisphericalshapes. The rigid porous structure may comprise a molded rigid porousstructure. The molded rigid porous structure may comprises at least oneof a disk, a helix or a tube coupled to the reservoir and configured torelease the therapeutic agent for the extended period.

FIG. 6C shows a rigid porous structure as in FIG. 6B incorporated into ascleral tack 601 as described in U.S. Pat. No. 5,466,233. The scleraltack comprises a head 602, a central portion 603 and a post 604. Thepost may comprise the reservoir 605 and the rigid porous structure 606as described above. The porous structure may comprise a molded conicalstructure having a sharp tip configured for insertion into the patient.Alternatively or in combination, the tip may be rounded.

FIG. 6E, shows a plurality of rigid porous structures as in FIG. 6Bincorporated with a drug delivery device for sustained release asdescribed in U.S. Pat. No. 5,972,369. The therapeutic device comprises areservoir 613 to contain the therapeutic agent and an impermeable andnon-porous outer surface 614. The reservoir is coupled to a rigid porousstructure 615 that extends to a distal end 617. The rigid porousstructure comprises an exposed area 616 on the distal end to release thetherapeutic agent, and the impermeable and non-porous outer surface mayextend to the distal end.

FIG. 6D shows a rigid porous structure as in FIG. 6B incorporated with adelivery device for sustained release as described in U.S. Pat. Pub.2003/0014036 A1. The drug delivery device comprises an inlet port 608 onthe proximal end and a hollow body 609 coupled to the inlet port. Thehollow body comprises many openings 612 that allow a solution injectedinto the inlet port to pass from the hollow body into a balloon 610. Theballoon comprises a distal end 611 disposed opposite the injection port.The balloon comprises a plurality of the rigid porous structures 607, asdescribed above. Each of the plurality of porous rigid structurescomprises a first surface exposed to the interior of the balloon and asecond surface configured to contact the vitreous. The calculated areacan be the combined area of the plurality of porous rigid structures asnoted above.

FIG. 6F shows a rigid porous structure as in FIG. 6B incorporated with anon-linear body member 618 for sustained release as described in U.S.Pat. No. 6,719,750. The non-linear member may comprise a helical shape.The non-linear member can be coupled to a cap 619 on the proximal end620. The non-linear member may comprise a lumen 621 filled withtherapeutic agent so as to comprise a reservoir 622. The porousstructure 623 can be disposed on a distal end 624 of the non-linearmember to release the therapeutic agent. The porous structure may belocated at additional or alternative locations of the non-linear member.For example a plurality of porous structures may be disposed along thenon-linear member at locations disposed between the cap and distal endso as to release therapeutic agent into the vitreous humor when the capis positioned against the sclera.

FIG. 6G shows porous nanostructures, in accordance with embodiments. Theporous structure 150 may comprise a plurality of elongate nano-channels156NC extending from a first side 150S1 of the porous structure to asecond side 150S2 of the porous structure. The porous structure 150 maycomprise a rigid material having the holes formed thereon, and the holesmay comprise a maximum dimension across such as a diameter. The diameterof the nano-channels may comprise a dimension across, for example fromabout 10 nm across, to about 1000 nm across, or larger. The channels maybe formed with etching of the material, for example lithographic etchingof the material. The channels may comprise substantially straightchannels such that the channel parameter F comprises about 1, and theparameters area A, and thickness or length L correspond to the combinedcross-sectional area of the channels and the thickness or length of theporous structure.

The porous structure 150 may comprise interconnecting nano-channels, forexample formed with a sintered nano-material.

The injection of therapeutic agent into the device 100 as describedherein can be performed before implantion into the eye or alternativelywhen the therapeutic device is implanted into the eye.

FIG. 7 shows a therapeutic device 100 coupled to an injector 701 thatremoves material from the device and injects therapeutic agent 702 intothe device. The injector picks up spent media 703 and refills theinjector with fresh therapeutic agent. The therapeutic agent is injectedinto the therapeutic device. The spent media is pulled up into theinjector. The injector may comprise a stopper mechanism 704.

The injector 701 may comprise a first container 702C to contain aformulation of therapeutic agent 702 and a second container 703C toreceive the spent media 703. Work in relation to embodiments suggeststhat the removal of spent media 703 comprising material from thecontainer reservoir of the therapeutic device can remove particulatefrom the therapeutic device, for example particles comprised ofaggregated therapeutic agent such as protein. The needle 189 maycomprise a double lumen needle with a first lumen coupled to the firstcontainer and a second lumen coupled to the second container, such thatspent media 703 passes from the container reservoir of device 100 to theinjector. A valve 703V, for example a vent, can be disposed between thesecond lumen and the second container. When the valve is open andtherapeutic agent is injected, spent media 703 from the containerreservoir of the therapeutic device 100 passes to the second containerof the injector, such that at least a portion of the spent media withinthe therapeutic device is exchanged with the formulation. When the valveis closed and the therapeutic agent is injected, a portion of thetherapeutic agent passes from the reservoir of the therapeutic deviceinto the eye. For example, a first portion of formulation of therapeuticagent can be injected into therapeutic device 100 when the valve is opensuch that the first portion of the formulation is exchanged withmaterial disposed within the reservoir; the valve is then closed and asecond portion of the formulation is injected into therapeutic device100 such that at least a portion of the first portion passes through theporous structure into the eye. Alternatively or in combination, aportion of the second portion of injected formulation may pass throughthe porous structure when the second portion is injected into the eye.The second portion of formulation injected when the valve is closed maycorrespond to a volume of formulation that passes through the porousstructure into the vitreous humor to treat the patient immediately.

The needle 189 may comprise a dual lumen needle, for example asdescribed with reference to FIG. 7A2 shown below.

FIG. 7A shows a therapeutic device 100 coupled to an injector 701 toinject and remove material from the device. The injector may comprise atwo needle system configured to insert into a container of the device.The injector may simultaneously inject therapeutic agent through thefirst needle 705 (the injection needle) while withdrawing liquid fromthe device through the second needle 706 (the vent needle). Theinjection needle may be longer and/or have a smaller diameter than thevent needle to facilitate removal of prior material from the device. Thevent needle may also be attached to a vacuum to facilitate removal ofprior material from the device.

FIG. 7A-1 shows a therapeutic device 100 comprising a penetrable barriercoupled to an injector needle 189 comprising a stop 189S that positionsthe distal end of the needle near the proximal end of the reservoir 130of the device to flush the reservoir with ejection of liquid formulationthrough the porous frit structure, in accordance with embodiments. Forexample, the injector needle may comprise a single lumen needle having abevel that extends approximately 0.5 mm along the shaft of the needlefrom the tip of the needle to the annular portion of the needle. Thestop can be sized and positioned along an axis of the needle such thatthe needle tip extends a stop distance 189SD into the reservoir asdefined by the length of the needle from the stop to the tip and thethickness of the penetrable barrier, in which the stop distance iswithin a range from about 0.5 to about 2 mm. The reservoir may extendalong an axis of the therapeutic device distance within a range fromabout 4 to 8 mm. A volume comprising a quantity of liquid formulationwithin a range from about 20 to about 200 uL, for example about 50 uLcan be injected into the therapeutic device with the needle tip disposedon the distal end. The volume of the reservoir can be less than theinjection volume of the formulation of therapeutic agent, such thatliquid is flushed through the porous structure 150. For example, thereservoir may comprise a volume within a range from about 20 to 40 uL,and the injection volume of the liquid formulation of therapeutic agentmay comprise about 40 to 100 uL, for example about 50 uL.

FIG. 7A-2 shows a therapeutic device comprising a penetrable barriercoupled to a needle 189 of an injector 701 to inject and remove materialfrom the device such that the liquid in the reservoir 130 is exchangedwith the injected formulation. The needle comprises at least one lumenand may comprise a concentric double lumen needle 189DL with a distalend coupled to the inner lumen to inject formulation of the therapeuticagent into the therapeutic device and a proximal vent 189V to receiveliquid into the needle when the formulation is injected. Alternatively,the vent may correspond to an opening on the distal end of the innerlumen of the needle and the outer lumen may comprise a proximal openingto inject therapeutic agent formulation into a proximal portion of thecontainer reservoir.

Work in relation to the injector embodiments indicates that a fillingefficiency of at least about 80%, for example 90% or more can beachieved with injector apparatus and needles as described above.

FIG. 7B-1 shows a side cross-sectional view of therapeutic device 100comprising a retention structure having a cross-section sized to fit inan elongate incision. The cross-section sized to fit in the elongateincision may comprise a narrow portion 120N of retention structure 120that is sized smaller than the flange 122. The narrow portion 120N sizedto fit in the elongate incision may comprise an elongate cross section120NE sized to fit in the incision. The narrow portion 120N may comprisea cross-section having a first cross-sectional distance across, or firstdimensional width, and a second cross-sectional distance across, orsecond dimensional width, in which the first cross-sectional distanceacross is greater than the second cross-sectional distance across suchthat the narrow portion 120N comprises an elongate cross-sectionalprofile.

The elongate cross section 120NE of the narrow portion 120N can be sizedin many ways to fit the incision. The elongate cross section 120NEcomprises a first dimension longer than a second dimension and maycomprise one or more of many shapes such as dilated slit, dilated slot,lentoid, oval, ovoid, or elliptical. The dilated slit shape and dilatedslot shape may correspond to the shape sclera tissue assumes when cutand dilated. The lentoid shape may correspond to a biconvex lens shape.The elongate cross-section of the narrow portion may comprise a firstcurve along an first axis and a second curve along a second axisdifferent than the first curve.

Similar to the narrow portion 120N of the retention structure, thecontainer reservoir may comprise a cross-sectional profile

FIG. 7B-2 shows an isometric view of the therapeutic device as in FIG.7B-1.

FIG. 7B-3 shows a top view of the therapeutic device as in FIG. 7B-1.

FIG. 7B-4 shows a side cross sectional view along the short side of theretention structure of the therapeutic device as in FIG. 7B-1.

FIG. 7B-5 shows a bottom view of the therapeutic device as in FIG. 7B-1implanted in the sclera.

FIG. 7B-5A shows a cutting tool 710 comprising a blade 714 having awidth 712 corresponding to perimeter 160P of the barrier 160 and theperimeter 160NP of the narrow portion. The cutting tool can be sized tothe narrow portion 120N so as to seal the incision with the narrowportion when the narrow portion is positioned against the sclera. Forexample, the width 712 may comprise about one half of the perimeter 160Pof the barrier 160 and about one half of the perimeter 160NP of thenarrow portion 160N. For example, the outside diameter of the tube ofbarrier 160 may comprise about 3 mm such that the perimeter of 160Pcomprises about 6 mm, and the narrow portion perimeter 160NP maycomprise about 6 mm. The width 712 of the blade 710 may comprise about 3mm such that the incision comprises an opening having a perimeter ofabout 6 mm so as to seal the incision with the narrow portion 160P.Alternatively, perimeter 160P of barrier 160 may comprise a sizeslightly larger than the incision and the perimeter of the narrowportion.

The retention structure comprises a narrow section 120N having a shortdistance 120NS and a long distance 120NL so as to fit in an elongateincision along the pars plana of the eye. The retention structurecomprises an extension 122. The extension of the retention structure120E comprises a short distance across 122S and a long distance across122S, aligned with the short distance 122NS and long distance 122NL ofthe narrow portion 120N of the retention structure 120. The narrowportion 120 may comprise an indentation 120I sized to receive thesclera.

FIGS. 7B-6A and 7B-6B show distal cross-sectional view and a proximalcross-sectional view, respectively, of therapeutic device 100 comprisinga non-circular cross-sectional size. The porous structure 150 can belocated on a distal end portion of the therapeutic device, and theretention structure 120 can be located on a proximal portion oftherapeutic device 100. The barrier 160 defines a size of reservoir 130.The barrier 160 and reservoir 130 may each comprise an elliptical oroval cross-sectional size, for example. The barrier 160 comprises afirst cross-sectional distance across reservoir 130, and a secondcross-sectional distance across reservoir 130, and the first distanceacross may extend across a long (major) axis of an ellipse and thesecond distance across may extend across a short (minor) axis of theellipse. This elongation of the device along one direction can allow forincreased drug in the reservoir with a decrease interference in vision,for example, as the major axis of the ellipse can be alignedsubstantially with the circumference of the pars plana region of the eyeextending substantially around the cornea of the eye, and the minor axisof the ellipse can be aligned radially with the eye so as to decreaseinterference with vision as the short axis of the ellipse extends towardthe optical axis of the eye corresponding to the patient's line of sightthrough the pupil. Although reference is made to an elliptical or ovalcross-section, many cross-sectional sizes and shapes can be used such asrectangular with a short dimension extending toward the pupil of the eyeand the long dimension extending along the pars plana of the eye.

The retention structure 120 may comprise structures corresponding tostructure of the cross-sectional area. For example, the extension 122may comprise a first distance across and a second distance across, withthe first distance across greater than the second distance across. Theextension may comprise many shapes, such as rectangular, oval, orelliptical, and the long distance across can correspond to the longdistance of the reservoir and barrier. The retention structure 120 maycomprise the narrow portion 120N having an indentation 120I extendingaround an access port to the therapeutic device, as described above. Theindentation 120I and extension 122 may each comprise an elliptical oroval profile with a first long (major) axis of the ellipse extending inthe first direction and a second short (minor) axis of the ellipseextending in the second direction. The long axis can be aligned so as toextend circumferentially along the pars plana of the eye, and the shortaxis can be aligned so as to extend toward the pupil of the eye, suchthat the orientation of device 100 can be determined with visualexamination by the treating physician.

FIG. 7B-6C shows an isometric view of the therapeutic device having aretention structure comprising a narrow portion 120N with an elongatecross-sectional size 120NE.

FIG. 7B-6D shows a distal end view of the therapeutic device as in FIG.7B-6C.

FIG. 7B-6E1 shows a side view of the short distance 120NS of the narrowportion 120N of the therapeutic device as in FIG. 7B-6C.

FIG. 7B-6E2 shows a side view of the long distance 120NL of the narrowportion 120N of the therapeutic device 100 as in FIG. 7B-6C.

FIG. 7B-6F shows a proximal view view of the therapeutic device as inFIG. 7B-6C.

FIG. 7B-6G to FIG. 7B-6I show exploded assembly drawings for thetherapeutic device 100 as in FIGS. 7B-6C to 7B-6F. The assembly drawingsof FIG. 7B-6G, FIG. 7B-6H and FIG. 7B-6I show isometric and thin sideprofiles views, respectively, of the elongate portion 120NE of thenarrow portion of the retention structure 120N. The therapeutic device100 has an elonagate axis 100A.

The penetrable barrier 184, for example the septum, can be inserted intothe acess port 180. The penetrable barrier may comprise an elasticmaterial sized such that the penetrable barrier can be inserted into theaccess port 180. The penetrable barrier may comprise one or more elasticmaterials such as siloxane or rubber. The pentrable barrier may comprisetabs 184T to retain the penetrable barrier in the acces port. Thepenetrable barrier 184 may comprise a beveled upper rim 184R sized toseal the access port 180. The access port 180 of the reservoir container130 may comprise a beveled upper surface to engage the beveled rim andseal the penetrable barrier against the access port 180 when the tabs184T engage an inner annular or elongate channel of the access port. Thepenetrable barrier 184 may comprise an opaque material, for example agrey material, for example silicone, such that the penetrable barriercan be visualized by the patient and treating physician.

The reservoir container 130 of the device may comprise a rigidbiocompatible material that extends at least from the retentionstructure to the rigid porous structure, such that the reservoircomprises a substantially constant volume when the therapeutic agent isreleased with the rigid porous structure so as to maintain a stablerelease rate profile, for example when the patient moves. Alternativelyor in combination, the reservoir container 130 may comprise an opticallytransmissive material such that the reservoir container 130 can betranslucent, for example transparent, such that the chamber of reservoir140 can be visualized when the device is loaded with therapeutic agentoutside the patient prior to implantation, for example when injectedwith a formulation of therapeutic agent prior to implantation in thephyscian's office. This visualization of the reservoir 140 can behelpful to ensure that the reservoir 140 is properly filled withtherapeutic agent by the treating physician or assistant prior toimplantation. The reservoir container may comprise one or more of manybiocomaptible materials such as acrylates, polymethylmethacrylate,siloxanes, metals, titanium stainless steel, polycarbonate,polyetheretherketone (PEEK), polyethylene, polyethylene terephthalate(PET), polyimide, polyamide-imide, polypropylene, polysulfone,polyurethane, polyvinylidene fluoride or PTFE. The biocompatiblematerial of the reservoir container may comprise an opticallytransmissive material such as one or more of acrylate, polyacrylate,methlymethacraylate, polymethlymethacrylate (PMMA), polyacarbonate orsiloxane. The reservoir container 130 can be machined from a piece ofmaterial, or injection molded, so as to form the retention structure 120comprising flange 122 and the elongate narrow portion 120NE. The flange122 may comprise a translucent material such that the physician canvisualize tissue under the flange to assess the patient and to decreaseappearance of the device 100 when implanted. The reservoir container 130may comprise a channel extending along axis 100A from the access port180 to porous structure 150, such that formulation injected into device100 can be release in accordance with the volume of the reservoir andrelease rate of the porous structure 150 as described herein. The porousstructure 150 can be affixed to the distal end of therapeutic device100, for example with glue. Alternatively or in combination, the distalend of the reservoir container 130 may comprise an inner diameter sizedto receive the porous structure 150, and the reservoir container 130 maycomprise a stop to postion the porous structure 150 at a predeterminedlocation on the distal end so as to define a predetermined size ofreservoir 140.

FIG. 7C-1 shows an expandable therapeutic device 790 comprisingexpandable barrier material 160 and support 160S in an expandedconfiguration for extended release of the therapeutic agent. Theexpanded configuration can store an increased amount of therapeuticagent, for example from about 30 uL to about 100 uL. The expandabledevice comprises a retention structure 120, an expandable reservoir 140.The support 160S may comprise a resilient material configured forcompression, for example resilient metal or thermoplastic.Alternatively, the expandable support may be bent when expanded. Theexpandable device comprises the porous structure 150 disposed on adistal end, and affixed to the expandable support. The expandable devicemay comprise an access port 180, for example with a penetrable barrier184. In the expanded configuration, the device is substantially clearfrom a majority of the optical path OP of the patient

The support 160S of the barrier 160 can provide a substantially constantvolume of the reservoir in the expanded configuration. The substantiallyconstant volume, for example +/−25%, can be combined with the releaserate index of the porous structure 150 so as to tune the expandedreservoir and porous structure to the volume of therapeutic agent to beinjected into the therapeutic device as described herein. The barrier160 may comprise a thin compliant material, for example a membrane, andthe support 160S can urge the barrier 160 to an expanded configurationso as to define the reservoir chamber having the substantially constantvolume.

FIG. 7C-1A shows the distal end portion of the support 160S. The support160S may comprise struts that extend to an annular flange 160SF thatsupports the porous structure 150 on the distal end of device 100.

FIG. 7C-1B shows the support 160S disposed inside the barrier 160 so asto provide the substantially constant expanded volume of the reservoirchamber.

FIG. 7C-1C shows the support 160S disposed along the inner surface ofthe barrier 160 so as to provide the substantially constant expandedvolume of the reservoir chamber. The support 160 can be bonded to thebarrier 160 in many ways, for example with a bonding agent such as glueor resin, or with thermal bonding. The support 160S can be disposed onthe outside of barrier 160.

FIG. 7C-2 shows the expandable therapeutic device 790 as in FIG. 7C-1 ina narrow profile configuration suitable for use in an injection lumen.

FIG. 7C-3 shows the expandable therapeutic device as in FIG. 7C-1 in anexpanded profile configuration, suitable for retention, for example withthe sclera.

FIGS. 7C-4A and 7C-4B show an expandable retention structure 792. Theexpandable retention structure 792 can be used with the expandabletherapeutic device 790, or with a substantially fixed reservoir andcontainer device as described above. The expandable retention structure792 comprises many compressible or expandable or resilient materials orcombinations thereof. The expandable retention structure 792 comprise anextension 120E that can expand from the narrow profile configuration tothe expanded configuration, for example with tabs and flanges comprisingresilient material. The upper portion can be inclined proximally and thedistal portion can be inclined distally, such that the retentionstructure expands to engage opposite sides of the sclera. The resilientmaterial may comprise a thermoplastic material, a resilient metal, ashape memory material, and combinations thereof.

FIG. 7D shows therapeutic device 100 comprising porous structure 150positioned in an eye 10 to deliver a therapeutic agent to a targetlocation on or near the retina 26, for example choroidalneovasculaturization of a lesion on or near the retina. For example, thelesion may comprise one or more buckling, folding, bending or separationof the retina from the choroid related to neovascularization ofcorresponding vascular tissue associated with blood supply to theretina, and the neovascular tissue corresponding to the lesion of theretina may be targeted. Work in relation to embodiments indicates thatthe vitreous humor 30 of the eye may comprise convective current flowsthat extend along flow paths 799. The convective flow paths may compriseflow channels. Although small molecules can be delivered to a targetlocation of the retina 26 in accordance with the flow paths, therapeuticagent comprising large molecules, for example with antibody fragments orantibodies, can be delivered substantially with the convective flowpaths as the molecular diffusion of large molecules in the vitreoushumor can be somewhat lower than small molecules.

The therapeutic device can be sized such that porous structure 150 ispositioned along a flow path extending toward a target location of theretina. The therapeutic agent can be released along the flow path, suchthat the flow of vitreous humor transports the therapeutic agent to theretina. The porous structure can be disposed on a distal portion of thetherapeutic device, for example on a distal end, and the reservoir 130can be sized for delivery for the extended time. The retention structure120 can be located on the proximal. The therapeutic device 100 can besized such that the porous structure is positioned in the flow patchcorresponding to the target region. The surgeon may identify a targetregion 798 of the retina, for example corresponding to a lesion, and thetherapeutic device 100 can be positioned along the pars plana or otherlocation such that the therapeutic agent is released to the targetregion.

FIG. 7E shows therapeutic device 100 comprising porous structure 150located on a proximal portion of the device to deliver a therapeuticagent to one or more of the ciliary body or the trabecular meshwork whenimplanted in the eye. The porous structure 150 can be located nearretention structure 120 such that the porous structure is positioned inthe vitreous substantially away from the flow paths extending to retina,as noted above. The porous structure can be located on a side of thetherapeutic device so as to release the therapeutic agent toward atarget tissue. While many therapeutic agents can be used, thetherapeutic agent may comprise a prostaglandin or analog, such asbimatoprost or latanoprost, such that the therapeutic agent can bereleased toward one or more of the ciliary body or trabecular meshworkwhen implanted in the vitreous humor with the retention structurecoupled to the sclera.

FIG. 7F shows therapeutic device 100 comprising porous structure 150oriented to release the therapeutic agent 110 away from the lens andtoward the retina. For example, the therapeutic agent 110 may comprise asteroid, and the steroid can be released from porous structure 150 awayfrom the lens and toward the retina. For example, the porous structurecan be oriented relative to an axis 100A of the therapeutic device. Theouter side of porous structure 150 can be oriented at least partiallytoward the retina and away from the lens, for example along a flow pathas described above so as to treat a target region of the retina. Thebarrier 160 can extend between the porous structure 160 and the lens ofthe eye when implanted such that release of therapeutic agent toward thelens can be inhibited with barrier 160. The retention structure 120 maycomprise a long distance across and a short distance across as describedabove. The porous structure can be oriented in relation to the short andlong distances of the extensions 122, such that the outer side of porousstructure 150 is oriented at least partially toward the retina and alongthe flow path when the long distance of the retention structure extendsalong the pars plana and the short distance extends toward the pupil.

FIG. 7G shows a kit 789 comprising a placement instrument 750, acontainer 780, and a therapeutic device 100 disposed within thecontainer. The reservoir of the therapeutic deviced 100 disposed in thecontainer may comprise a non-therapeutic solution, for example saline,such that the channels of the porous structure comprise liquid water toinhibit bubble formation when the formulation of therapeutic agent isinjected into the device 100. The kit may also comprise the syringe 188,needle 189 and stop 189S to insert the needle tip to a maximum stopdistance within the reservoir as described above. The kit may containinstructions for use 789I, and may contain a container 110C comprising aformulation of therapeutic agent.

Tuning of Therapeutic Device for Sustained Release Based on an Injectionof a Formulation

The therapeutic device 100 can be tuned to deliver a target therapeuticconcentration profile based on the volume of formulation injected intothe device. The injected volume may comprise a substantially fixedvolume, for example within about +/−30% of an intended predeterminedtarget volume. The volume of the reservoir can be sized with the releaserate index so as to release the therapeutic agent for an extended timesubstantially greater than the treatment time of a corresponding bolusinjection. The device can also be tuned to release the therapeutic agentbased on the half life of the therapeutic agent in the eye. The devicevolume and release rate index comprise parameters that can be tunedtogether based on the volume of formulation injected and the half lifeof the therapeutic agent in the eye. The following equations can be usedto determine therapeutic device parameters suitable for tuning thedevice.Rate=Vr(dCr/dt)=−D(PA/TL)Cr

-   where Rate=Rate of release of therapeutic agent from device-   Cr=concentration of therapeutic agent in reservoir-   Vr=volume of reservoir-   D=Diffusion constant    PA/TL=RRI-   P=porosity-   A=area-   T=tortuosity=F=channel parameter.-   For a substantially fixed volume injection,    Cr0=(Injection Volume)(Concentration of Formulation)/Vr-   Where Cr0=initial concentration in reservoir following injection of    formulation-   For Injection Volume=50 uL    Cr0=(0.05 mL)(10 mg/mL)/Vr (1000 ug/1 mg)=500 ug/Vr    Rate=x(500 ug)exp(−xt)-   where t=time    x=(D/Vr)(PA/TL)-   With a mass balance on the vitreous    Vv(dCv/dt)=Rate from device=kVvCv-   where Vv=volume of vitreous (about 4.5 ml)-   Cv=concentration of therapeutic agent in vitreous-   k=rate of drug from vitreous (proportional to 1/half life of drug in    vitreous)-   For the situation appropriate for the embodiments as described    herein where Cv remains substantially constant and changes slowly    with time (i.e. dCv/dt is approximately 0),    Cv=(Rate from device)/(kVv)-   Since kVv is substantially constant, the max value of Cv will    correspond to conditions that maximize the Rate from the device. At    a given time since injection into the device (e.g., 180 days), the    maximum Cv is found at the the value of x that provides the maximum    rate. The optimal value of x satisfies    d(Rate)/dx=0 at a given time.    Rate=500(x)exp(−xt)=f(x)g(x) where f(x)=500x and g(x)=exp (−xt)    d(Rate)/dx=f′(x)g(x)+f(x)g′(x)=500(1−xt)exp(−xt)-   For a given time, t, d(Rate)/dx=0 when 1−xt=0 and xt=1-   The rate is maximum when (D/Vr)(PA/TL)t=1.-   For a given volume, optimal PA/TL=optimal RRI=Vr/(Dt)-   Therefore the highest Cv at a given time, t, occurs for the optimal    RRI=(PA/FL) for a given Vr.-   Also, the ratio (Vr)/(RRI)=(Vr)/(PA/TL)=Dt will determine the    optimal rate at the time.

The above equations provide approximate optimized values that, whencombined with numerical simulations, can provide optimal values of Vrand PA/TL. The final optimum value can depend on additional parameters,such as the filling efficiency.

The above parameters can be used to determine the optimal RRI, and thetherapeutic device can be tuned to the volume of formulation injectedinto the device with a device reservoir volume and release rate indexwithin about +/−50% of the optimal values, for example +/−30% of theoptimal values. For example, for an optimal release rate index of theporous structure and an optimal reservoir volume sized to receive apredetermined quantity of therapeutic agent, e.g. 50 uL, so as toachieve therapeutic concentrations above a minimum inhibitoryconcentration for a predetermined extended time such as 90 days, themaximum volume of the reservoir can be limited to no more than abouttwice the optimal volume. This tuning of the reservoir volume and theporous structure to the injected volume of the commercially availableformulation can increase the time of release of therapeutic amounts fromthe device as compared to a much larger reservoir volume that receivesthe same volume of commercially available injectable formulation.Although many examples as described herein show a porous frit structureand reservoir volume tuned together to receive a quantity of formulationand provide release for an extended time, the porous structure tunedwith the reservoir may comprise one or more of a porous frit, apermeable membrane, a semi-permeable membrane, a capillary tube or atortuous channel, nano-structures, nano-channels or sinterednano-particles, and a person of ordinary skill in the art can determinethe release rate characteristics, for example a release rate index, soas to tune the one or more porous structures and the volume to receivethe quantity of the formulation and release therapeutic amounts for anextended time.

As an example, the optimal RRI at 180 days can be determined for areservoir volume of about 125 uL. Based on the above equations(Vr/Dt)=optimal RRI, such that the optimal RRI at 180 days is about0.085 for the 50 uL formulation volume injected into the device. Thecorresponding Cv is about 3.19 ug/mL at 180 days based on the Rate ofdrug released from the device at 180 days and the rate of the drug fromthe vitreous (k corresponding to a half life of about 9 days). A devicewith a container reservoir volume of 63 uL and RRI of 0.044 will alsoprovide the optimal Cv at 180 days since the ratio of Vr to PA/TL isalso optimal. Although an optimal value can be determined, thetherapeutic device can be tuned to provide therapeutic amounts of drugat a targeted time, for example 180 days, with many values of thereservoir volume and many values of the release rate index near theoptimal values, for example within about +/−50% of the optimal values.Although the volume of the reservoir can be substantially fixed, thevolume of the reservoir can vary, for example within about +/−50% aswith an expandable reservoir such as a balloon reservoir.

The half life of the drug in the vitreous humor of the eye can bedetermined based on the therapeutic agent and the type of eye, forexample human, rabbit or monkey, such that the half life may bedetermined based on the species of the eye, for example. With at leastsome animal models the half life of the therapeutic agent in thevitreous humor can be shorter than for human eyes, for examply by afactor of about two in at least some instances. For example, thehalf-life of the therapeutic agent Lucentis™ (ranibizumab) can be aboutnine days in the human eye and about two to four days in the rabbit andmonkey animal models. For small molecules, the half life in the vitreoushumor of the human eye can be about two to three hours and can be aboutone hour in the monkey and rabbit animal models. The therapeutic devicecan be tuned to receive the volume of formulation based on the half lifeof the therapeutic agent in the human vitreous humor, or an animalvitreous humor, or combinations thereof. Based on the teachingsdescribed herein, a person of ordinary skill in the art can determineempirically the half life of the therapeutic agent in the eye based onthe type of eye and the therapeutic agent, such that the revervoir andporous structure can be tuned together so as to receive the volume offormulation and provide therapeutic amounts for the extended time.

EXPERIMENTAL Example 1

FIG. 8 shows reservoirs with exit ports of defined diameters fabricatedfrom 1 mL syringes with Luer-Lok™ tips and needles of varying diameter.The needles were trimmed to a total length of 8 mm, where 2 mm extendedbeyond the needle hub. Metal burrs were removed under a microscope. FIG.8-1 shows the needles attached to syringes which were then filled with asolution of 2.4 mg/mL fluorescein sodium, molecular weight 376 Da, inphosphate buffer (Spectrum Chemicals, B-210.). Bubbles were removed andthe syringes were adjusted to be able to dispense 0.05 mL. The shape ofthe resulting reservoir is shown in FIG. 8-1. The first expanded regionis defined by the inside of the needle hub and the tip of the syringe.The second expanded region is inside the syringe. The total volume ofthe reservoir is 0.14 mL.

Once filled, the outside of the reservoirs were rinsed of excessfluorescein by submerging in PBS.

FIG. 8-2 shows the reservoirs placed into 4 mL vials containing 1.5 mLbuffer at room temperature. Collars cut from rubber tubing were placedaround the syringe barrels to position the top of the reservoir to matchthe height of buffer in the vial to avoid any pressure differential. Thetops of the vials were sealed with parafilm to avoid evaporation. Atperiodic intervals, the reservoirs were moved to new vials containingbuffer. The amount of fluorescein transported from the reservoir throughthe exit port was determined by measuring the amount of fluorescein inthe vials via absorption of visible light (492 nm).

Example 1

TABLE 1C Release of Fluorescein through Exit Port Needle ReleaseReservoir Needle ID Area Rate Number Gauge (mm) (mm{circumflex over( )}2) (ug/day) 1 18 0.838 0.552 10.8 2 18 0.838 0.552 9.4 3 23 0.3180.079 1.0 4 23 0.318 0.079 1.2 5 30 0.14 0.015 0.6 6 30 0.14 0.015 0.6

The initial release rate (averaged over 0.5-4 days) is proportional tothe area of the exit port opening.

The cumulative amount released into the vials is shown in FIG. 9. Theamount released in a week ranged from 2 to 20%. An average delivery ratewas determined from the slope for data collected between 0.5 and 4.5days and is reported in Table 1C. FIG. 10 shows that the initial releaserate is approximately proportional to the area of the exit port opening.

Example 2

FIG. 11 shows reservoirs with a porous membrane fabricated by cuttingoff the Luer-Lok tip on 1 mL syringes. The end of the syringe wassmoothed and beveled. A nylon membrane with 0.2 μm pore size was placedover the end of the syringe and secured with a piece of silicone tubing.The inner diameter of the syringe was 4.54 mm, yielding an exposedmembrane area of 16 mm². The piston was removed so that approximately100 mL of 300 mg/mL bovine serum albumin (BSA, Sigma A7906-100G) in PBScould be added. The piston was replaced and moved to remove the air andto push a small amount of the liquid through the membrane. The outsideof the membrane and syringe was rinsed by submerging briefly in water.The reservoirs were then placed into 15 mL vials containing 5 mL PBS.The tops of the vials were sealed with parafilm to avoid evaporation. Atperiodic intervals of 0.5-1 day, the reservoirs were moved to new vialscontaining PBS. Diffusion through the membrane was determined bymeasuring the amount of BSA that accumulated in the vials via absorptionof visible light (280 nm). The delivery rates from two replicates areshown in FIG. 11-1. This data suggests that therapeutic agents ofinterest with molecular weight on the order of 100 kDa will transporteasily through porous membranes with pore sizes of 0.2 um.

Example 3

An experiment was performed to screen chromatographic media (Bio-Rad)for binding to Human IgG (Jackson ImmunoResearch, ChromPure). Columnswere packed with the ten media listed below and were equilibrated in 20mM acetate buffer pH 4.5.

TABLE 2 Macro-Prep t-Butyl HIC Support Macro-Prep DEAE Support CHTCeramic Hydroxyapatite Type I 40 um Macro-Prep CM Support Macro-PrepMethyl HIC Support Macro-Prep Ceramic Hydroxapatite Type II 40 umUNOsphere S Cation Exchange Support UNOsphere Q Strong Anion ExchangeSupport Macro-Prep High S Support Macro-Prep High Q Support

Then, 0.5 mL aliquots of 1 mg/mL antibody in 20 mM acetate buffer pH 4.5were gravity-driven through the column and the collected solution wasassessed qualitatively for color change using a BCA™ protein assay kit(Pierce). Of the media tested, Macro-Prep CM Support, Macro-Prep High SSupport, and Macro-Prep Ceramic Hydroxapatite Type II 40 um eachsuccessfully bound IgG. Subsequently, PBS was washed through the columnsand the IgG was released from all three of these media.

Future Exit Port Studies

The experiments described in Examples 1-3 can be repeated with agitationto explore the impact of mixing induced by eye movement. In addition,the experiments can be performed at body temperature where deliveryrates would be expected to be higher based upon faster diffusion ratesat higher temperature.

Diffusion rates of BSA (MW 69 kDa) should be representative of diffusionrates of Lucentis™ and Avastin™, globular proteins with MW of 49 and 150kDa, respectively. Selected experiments could be repeated to confirmindividual delivery rates of these therapeutic agents.

Device prototypes closer to the embodiments described in the body of thepatent could be fabricated from metals (e.g., titanium or stainlesssteel) or polymers (e.g., silicone or polyurethane). Exit ports ofdefined areas can be created via ablation or photo-etching techniques.In the case of polymers, exit ports can also be created by molding thematerial with a fine wire in place, followed by removal of the wireafter the polymer is cured. Access ports can be created using membranesof silicone or polyurethane. Needle stops and flow diverters can befabricated from metal or a rigid plastic.

Device prototypes can be tested with methods similar to those describedin Example 1. Drug delivery rates can be measured for pristine devicesas well as devices that have been refilled. Methods such as absorbanceand fluorescence can be used to quantitate the amount of therapeuticagent that has been delivered as a function of time. Enzyme-Linked

ImmunoSorbent Assays (ELISA) can be used to monitor the stability of thebiological therapeutic agent in the formulations at 37° C. and can beused to determine the concentration of biologically active therapeuticagent delivered as a function of time.

Future Membrane Studies

Experiments could be performed with a range of candidates to identifymembranes that 1) would be a barrier to bacteria and cells without muchresistance during refilling; 2) may contribute to controlling thedelivery rate of the therapeutic agent; and 3) would be biocompatible.Candidate membranes would have pore sizes of 0.2 μm or smaller,approaching the size of the therapeutic agents. A variety of fixturescan be used to secure a membrane between a donor solution and a receiversolution to measure permeation rates. In addition, performance ofmembranes can be tested in device prototypes using methods similar towhat was done in Example 3.

Porous membranes could include cellulose acetate, nylon, polycarbonate,and poly(tetrafluoroethylene) (PTFE), in addition to regeneratedcellulose, polyethersulfone, polyvinylidene fluoride (PVDF).

Developing Binding Formulations and Conditions

Once media and conditions have been screened via the batch orflow-through methods, devices can be fabricated containing the bindingmedia in place or with binding media injected along with the therapeuticagent. Formulations can be prepared with the desired excipients, andtherapeutic agent delivery rates can be monitored similarly to themethod used in Example 1.

Additional media to test for binding include, ion exchange andbioaffinity chromatography media based on a hydrophilic polymericsupport (GE Healthcare) that bind proteins with high capacity, and ahydrophilic packing material from Harvard Apparatus made from poly(vinylalcohol) that binds more protein than silica. Other candidates would beknown to those knowledgeable in the art.

A change in pH could modulate the binding of antibody to media. Forexample, binding of antibody would be expected in a formulation withcationic exchange media at an acidic pH. As the pH becomes more neutral,the antibody may be released from the media. Formulations could betested that provide acidic pH for finite durations (i.e., a few months).Once the pH has become neutral, the release of antibody from the bindingmedia could drive a higher release rate, resulting in a more constantrelease rate profile.

The binding media itself may have some buffering capacity that coulddominate until physiological buffer diffuses into the device.

Alternatively, the formulation could include a buffer with a bufferingcapacity selected to dominate during the first few months. With time,the formulation buffer will diffuse out of the device and physiologicalbuffer will diffuse into the device, which will result in a change of pHtowards physiological pH (i.e., neutral). The kinetics of this changecan be modulated by use of a polymeric buffer, with a higher molecularweight buffer remaining in the device for longer periods of time.Polypeptides are attractive as biocompatible polymeric buffers becausethey degrade to amino acids. Buffers are optimal near their pKa. Thetable below lists the pKa of the side chains of amino acids of interest.

TABLE 3 Amino Acid pKa of side chain L-Aspartic Acid 3.8 L-Glutamic Acid4.3 L-Arginine 12.0 L-Lysine 10.5 L-Histidine 6.08 L-Cysteine 8.28L-Tyrosine 10.1

The formulation could include a polyester, such as PLGA, or otherbiodegradable polymers such as polycaprolactone orpoly-3-hydroxybutyrate, to generate hydrogen ions for a finite amount oftime. The degradation rate could be modulated by, for example, changingthe composition or molecular weight of the PLGA, such that thedegradation is completed within a few months, contributing to reachingneutral pH in the last few months of delivery.

The pH could also be modulated electrochemically. Suitable electrodematerials include inert or non-consumable materials such as platinum orstainless steel. Water hydrolysis occurs at the electrode interfaces andthe products of hydrolysis are hydronium ions at the anode and hydroxylions at the cathode.

Rationale for Device Length

At least some device designs do not extend more than about 6 mm into thevitreous so as to minimize interference with vision. In addition, it canbe beneficial to have the device extend into the vitreous since thendrug can be released a distance from the walls of the globe.Macromolecules, such as antibodies, are primarily eliminated from thevitreous by a convection process rather than a diffusion process. (seeComputer Simulation of Convective and Diffusive Transport ofControlled-Release Drugs in the vitreous Humor, by Stay, M S; Xu, J,Randolph, T W; and V H Barocas, Pharm Res 2003, 20(1), pp. 96-102.)Convection can be driven by the pressure generated by the secretion ofaqueous humor by the ciliary body, with flow in the vitreous directedtowards the retina. With exit ports extending into the vitreous, it maybe more likely that drug will be convected towards the back of the eyeand the central retina, as opposed to a device with ports flush with theglobe likely delivering more of the therapeutic agent to the peripheralretina.

Example 4 Comparison of Predicted vs. Measured Release Rates for aReservoir with One Orifice

The release study described in Example 1 using 23 and 30 gauge needleswas continued through ten weeks. The results are compared with a modelrelating the change of concentration in the reservoir to the releaserate from the reservoir based upon Fick's Law of diffusion. This simplemodel assumes the concentration in the reservoir is uniform and theconcentration in the receiving fluid or vitreous is negligible. Solvingthe differential equation yields the following cumulative release of atherapeutic agent from a reservoir with one orifice:Cumulative Release=1−cR/cR0=1−exp ((−D A/L V _(R))t),

-   where:-   cR=Concentration in reservoir-   V_(R)=Volume of reservoir-   D=Diffusion coefficient-   A=Area of orifice-   L=Thickness of orifice-   t=Time

FIG. 12 shows the cumulative amount released into the vials over 10weeks and the predicted cumulative amount release. These data show thatthe release from model devices generally agrees with the trend predictedby this model with no adjustable fitting parameters.

Example 5 Release of Protein Through a Cylindrical Sintered PorousTitanium Cylinder

Reservoirs were fabricated from syringes and sintered porous titaniumcylinders (available from Applied Porous Technologies, Inc., MottCorporation or Chand Eisenmann Metallurgical). These were sinteredporous cylinders with a diameter of 0.062 inches and a thickness of0.039 inches prepared from titanium particles. The porosity is 0.17 withmean pore sizes on the order of 3 to 5 micrometers. The porous cylinderis characterized as 0.2 media grade according to measurements of bubblepoint. The porous cylinders were press-fit into sleeves machined fromDelrin. The sleeves exposed one entire planar face to the solution inthe reservoir and the other entire planar face to the receiver solutionin the vials, corresponding to an area of 1.9 square millimeters. Thetips were cut off of 1 mL polypropylene syringes and machined to accepta polymer sleeve with outer diameter slightly larger than the innerdiameter of the syringe. The porous cylinder/sleeve was press-fit intothe modified syringe.

A solution was prepared containing 300 mg/mL bovine serum albumin (BSA,Sigma, A2153-00G) in phosphate buffered saline (PBS, Sigma, P3813).Solution was introduced into the syringes by removing the piston anddispensing approximately 200 microliters into the syringe barrel.Bubbles were tapped to the top and air was expressed out through theporous cylinder. Then BSA solution was expressed through the porouscylinder until the syringe held 100 uL as indicated by the markings onthe syringe. The expressed BSA solution was wiped off and then rinsed bysubmerging in PBS. The reservoirs were then placed into 4 mL vialscontaining 2 mL PBS at room temperature. Collars cut from siliconetubing were placed around the syringe barrels to position the top of thereservoir to match the height of PBS. The silicone tubing fit inside thevials and also served as a stopper to avoid evaporation. At periodicintervals, the reservoirs were moved to new vials containing PBS. Theamount of BSA transported from the reservoir through the porous cylinderwas determined by measuring the amount of BSA in the vials using a BCA™Protein Assay kit (Pierce, 23227).

FIG. 13 shows the measured cumulative release of BSA through a sinteredporous titanium disc and a prediction from the model describing releasethrough a porous body. The Channel Parameter of 1.7 was determined via aleast squares fit between the measured data and the model (MicroSoftExcel). Since the porous cylinder has equal areas exposed to thereservoir and receiving solution, the Channel Parameter suggests atortuosity of 1.7 for porous titanium cylinders prepared from 0.2 mediagrade.

FIG. 13-1 shows the measured cumulative release of BSA of FIG. 13measured to 180 days. The Channel Parameter of 1.6 was determined via aleast squares fit between the measured data and the model (MicroSoftExcel). This corresponds to a Release Rate Index of 0.21 mm. Since theporous cylinder has equal areas exposed to the reservoir and receivingsolution, the Channel Parameter corresponds to an effective path lengthchannel parameter of 1.6 and suggests a tortuosity of 1.6 for poroustitanium cylinders prepared from 0.2 media grade.

Example 6 Release of Protein Through Masked Sintered Porous TitaniumCylinders

Reservoirs were fabricated from syringes and porous sintered titaniumcylinders similar to that described in Example 5. The porous sinteredtitanium cylinders (available from Applied Porous Technologies, Inc.,Mott Corporation or Chand Eisenmann Metallurgical) had a diameter of0.082 inch, a thickness of 0.039 inch, a media grade of 0.2 and wereprepared from titanium particles. The porosity is 0.17 with mean poresizes on the order of 3 to 5 micrometers. The porous cylinder ischaracterized as 0.2 media grade according to measurements of bubblepoint. The porous cylinders were press fit into sleeves machined fromDelrin. The sleeves exposed one entire planar face to the solution inthe reservoir and the other entire planar face to the receiver solutionin the vials, corresponding to an area of 3.4 square millimeters. Thetips were cut off of 1 mL polycarbonate syringes and machined to accepta polymer sleeve with outer diameter slightly larger than the innerdiameter of the syringe. The porous cylinder/sleeve was press fit intothe modified syringe. A kapton film with adhesive was affixed to thesurface exposed to the receiving solution to create a mask and decreasethe exposed area. In the first case, the diameter of the mask was 0.062inches, exposing an area of 1.9 square millimeters to the receivingsolution. In a second case, the diameter of the mask was 0.027 inches,exposing an area of 0.37 square millimeters.

Three conditions were run in this study: 1) 0.062 inch diameter mask,100 uL donor volume, at room temperature in order to compare withreservoirs with unmasked porous cylinders in Example 5; 2) 0.062 inchdiameter mask, 60 uL donor volume, at 37° C.; and 3) 0.027 inch diametermask, 60 uL donor volume, at 37° C. The syringes were filled with asolution containing 300 mg/mL bovine serum albumin (BSA, Sigma,A2153-00G) in phosphate buffered saline (Sigma, P3813), similar toExample 5. In addition, 0.02 wt % of sodium azide (Sigma, 438456-5G) wasadded as a preservative to both the BSA solution placed in thereservoirs and the PBS placed in the receiving vials and both solutionswere filtered through a 0.2 micron filter. This time, the amount of BSAsolution dispensed into the syringe was weighed and the amount expressedthrough the porous cylinder was determined by rinsing and measuring theamount of BSA in the rinse. Assuming unit density for the BSA solution,the amount dispensed was 113+/−2 uL (Condition 1) and 66+/−3 uL(Condition 2). Subtracting off the amount in the rinse yielded a finalreservoir volume of 103+/−5 uL (Condition 1) and 58+/−2 uL (Condition2). The reservoirs were then placed into 5 mL vials containing 1 mL PBSat 37° C. in a heating block. At periodic intervals, the reservoirs weremoved to new vials containing PBS and the BSA concentrations weredetermined in the receiving solutions using the method described inExample 5.

FIG. 14 shows the cumulative release of BSA protein through a maskedsintered porous Titanium disc at Condition 1 (0.062 inch diameter mask,100 uL donor volume, at room temperature) is faster than the releasethrough an unmasked porous cylinder with the same exposed area (datafrom Example 5). Predictions are also shown using the Channel Parameterof 1.7 determined in Example 5, BSA diffusion coefficient at 20° C.(6.1e-7 cm²/s), reservoir volume of 100 uL, and the area of the porouscylinder exposed to the receiver solution (A=1.9 mm²) or the area of theporous cylinder exposed to the reservoir (A=3.4 mm²). The data for themasked porous cylinder matches more closely with larger area exposed tothe reservoir. Hence, this mask with width of 0.7 mm is not sufficientto reduce the effective area of the porous cylinder for the dimensionsof this porous cylinder.

FIG. 15 shows the cumulative release of BSA protein through a maskedsintered porous titanium cylinder at Condition 2 (0.062 inch diametermask, 60 uL donor volume, at 37° C.). The figure also displayspredictions using the Channel Parameter of 1.7 determined in Example 5,BSA diffusion coefficient at 37° C. (9.1e-7 cm²/s), reservoir volume of58 uL, and the area of the porous cylinder exposed to the receiversolution (A=1.9 mm²) or the area of the porous cylinder exposed to thereservoir (A=3.4 mm²). Again, the data for this masked porous cylindermatches more closely with larger area exposed to the reservoir. Theconsistency of the data with the model at two temperatures supports howthe model incorporates the effect of temperature.

FIG. 16 shows the cumulative release of BSA protein through a maskedsintered porous titanium cylinder at Condition 3 (0.027 inch diametermask, 60 uL donor volume, at 37° C.). The figure also displayspredictions using the Channel Parameter of 1.7 determined in Example 5,BSA diffusion coefficient at 37° C. (9.1e-7 cm²/s), reservoir volume of58 uL, and the area of the porous cylinder exposed to the receiversolution (A=0.37 mm²) or the area of the porous cylinder exposed to thereservoir (A=3.4 mm²). This mask achieves a release rate correspondingto an effective area in between the area exposed to the reservoir andthe area exposed to the receiver solution. A combination of the resultsin FIGS. 15 and 16 demonstrate that slower release is achieved using amask that exposes a smaller area to the receiver solution.

FIGS. 13-16 show an unexpected result. Masking of the area of the porousfrit structure so as to decrease the exposed area of the porousstructure decreased the release rate less than the corresponding changein area. The release rate through the porous structure correspondssubstantially to the interconnecting channels of the porous fritstructure disposed between the first side exposed to the reservoir andthe second side exposed to the receiver solution, such that the rate ofrelease is maintained when a portion of the porous frit structure iscovered. The rate of release of the interconnecting channels correspondssubstantially to an effective area of the porous frit structure, and theeffective area may correspond to an effective area of theinterconnecting channels within the porous structure as shown above. Asthe rate of release is dependent upon the interconnecting channels, therelease rate can be maintained when at least some of the channels areblocked, for example with coverage of a portion of the porous structureor blocking of a portion of the interconnecting channels with particles.

Example 7 Release of Protein Through Sintered Porous Stainless SteelCylinder (Media Grade 0.1)

Prototype devices were fabricated from tubing and sintered porousstainless steel cylinders (available from Applied Porous Technologies,Inc., Mott Corporation or Chand Eisenmann Metallurgical) which arecylindrical with diameter 0.155 inch and thickness 0.188 inch preparedfrom 316L stainless steel particles. The porous cylinder ischaracterized as 0.1 media grade according to measurements of bubblepoint. This study was performed with these large, off-the-shelf porouscylinders with an area of 12 mm² in order to characterize the resistiveproperties of 0.1 media grade stainless steel.

These devices were prepared using Teflon-FEP heat shrink tubing (Zeus,#37950) and a hot air gun to shrink around the porous cylinders on oneend and a custom prepared septum on the other end (Nusil MED1 4013silicone molded to 0.145 inch diameter). The reservoir volume (46+/−2uL) was determined from the difference in weight between empty systemsand systems loaded with PBS. The PBS was loaded by submerging thesystems in PBS and drawing a vacuum. The systems were then sterilized byheating to 250° F., 15 psi for 15 minutes, submerged in PBS inmicrocentrifuge tubes placed in a pressure cooker (Deni, 9760). Two 30Gneedles were inserted into the septum to displace the PBS with BSAsolution. One was used to inject the BSA solution and the other was bentand used as a vent for the displaced PBS. Sufficient BSA solution wasinjected to fill the needle hub of the vent to approximately ¾ full.Similar to Example 6, the BSA and PBS contained sodium azide and thenominal concentration was 300 mg/mL BSA. The devices were placed into1.5 mL microcentrifuge tubes containing 1 mL PBS and kept at 37° C. in aheating block. Pieces of silicone tubing (tight fit with inside of tube,hole for septum) were used to suspend the devices in the PBS with thebottom of the septum approximately the same height as the PBS. Theconcentrations in the first tubes contained BSA from the filling processand were discarded. At periodic intervals, the devices were moved to newtubes containing PBS and the BSA concentrations were determined in thereceiving solutions using the method described in Example 5.

FIG. 17 displays the measured cumulative release of BSA through the 0.1media grade stainless steel sintered titanium discs. Since the Porosity,P, is not available from the vendor at this time, a single parameter ofPorosity divided by Channel Parameter was determined by least squaresfit of the model to the data. Since the sintered porous structure iscylindrical, the Channel Parameter can be interpreted as the Tortuosity,T, and P/T was determined to be equal to 0.07.

Example 8 Release of Protein Through a Sintered Porous Stainless SteelCylinder (Media Grade 0.2)

Prototype devices were fabricated from tubing and sintered porousstainless steel cylinders (available from Applied Porous Technologies,Inc., Mott Corporation or Chand Eisenmann Metallurgical) which arecylindrical with diameter 0.031 inch, and thickness 0.049 inch preparedfrom 316L stainless steel particles. The porous cylinder ischaracterized as 0.2 media grade according to measurements of bubblepoint. This porous cylinder was obtained as a custom order withproperties determined from a previous study with a large diameter 0.2media grade porous stainless steel cylinder (data no shown) andpredictions based on the model described herein. The area of each faceof this porous cylinder is 0.5 mm².

These devices were prepared using Teflon-FEP heat shrink tubing (Zeus,0.125 inch OD) and a hot air gun to shrink around the porous cylinder onone end and a custom prepared septum on the other end (Nusil MED1 4013silicone molded to 0.113 inch diameter). The reservoir volume (17+/−1uL) was determined from the difference in weight between empty systemsand systems filled with PBS. The PBS was loaded by submerging thesystems in PBS and drawing a vacuum. Dry devices were submerged in PBSin microcentrifuge tubes and sterilized by heating to 250° F., 15 psifor 15 minutes in a pressure cooker (Deni, 9760). Two 30G needles wereinserted into the septum to fill the devices with PBS. One was used toinject the PBS and the other was bent and used as a vent. After weighingthe PBS filled devices, two new needles were inserted through the septumand sufficient BSA solution was injected to fill the needle hub of thevent to approximately ¾ full. The remaining details of the experimentare the same as Example 7.

FIG. 18A displays the measured cumulative release of BSA through the 0.2media grade sintered porous stainless steel cylinder. A single parameterof Porosity divided by Channel Parameter was determined to be 0.12 byleast squares fit of the model to the data. Since the sintered porousstructure is cylindrical, the Channel Parameter can be interpreted aseffective length of the interconnecting channels that may correspond theTortuosity, T. Using the Porosity of 0.17 determined by the vendor, theeffective length of the channel that may correspond to the Tortuositywas determined to be 1.4. Furthermore, this corresponds to a PA/FL ratio(Release Rate Index) of 0.0475 mm.

FIG. 18B displays the measured cumulative release of BSA through the 0.2media grade sintered porous stainless steel cylinder for 180 days. Asingle parameter of Porosity divided by Channel Parameter was determinedto be 0.10 by least squares fit of the model to the data. Since thesintered porous structure is cylindrical, the Channel Parameter can beinterpreted an effective length of the inter-connecting channels thatmay correspond to the Tortuosity, T. Using the Porosity of 0.17determined by the vendor, the effective channel length of theinter-connecting channels that may correspond to the Tortuosity wasdetermined to be 1.7. Furthermore, this corresponds to a PA/FL ratio(Release Rate Index) of 0.038 mm.

Example 9 Calculations of Lucentis™ Concentrations in the Vitreous

The vitreous concentrations of a therapeutic agent can be predictedbased on the equations described herein. Table 4 shows the values of theparameters applied for each of Simulation 1, Simulation 2, Simulation 3,Simulation 4, and Simulation 5. The half-life and vitreous volumecorrespond to a monkey model (J. Gaudreault et al., PreclinicalPharmacokinetics of Ranibizumab (rhuFabV2) after a Single IntravitrealAdministration, Invest Ophthalmol Vis Sci 2005; 46: 726-733) (Z. Yao etal., Prevention of Laser Photocoagulation Induced ChoroidalNeovascularization Lesions by Intravitreal Doses of Ranibizumab inCynomolgus Monkeys, ARVO 2009 abstract D906). The parameter PA/FL can bevaried to determine the release rate profile. For example, the value ofA can be about 1 mm², the porosity can be about 0.1 (PA=0.1 mm²) and thelength about 1 mm and the channel fit parameter that may correspond totortuousity can be about 2 (FL=2 mm), such that PA/TL is about 0.05 mm.A person of ordinary skill in the art can determine empirically thearea, porosity, length and channel fit parameter for extended release ofthe therapeutic agent for the extended period based on the teachingsdescribed herein.

TABLE 4A Values Values Values Values Values Parameter Simulation 1Simulation 2 Simulation 3 Simulation 4 Simulation 5 Diffusion coeff(cm2/s) 1.0E−06 1.0E−06 1.0E−06 1.0E−06 1.0E−06 Initial Loading (ug/mL)10000 10000 10000 10000 10000 Reservoir Vol (ml) 0.05 0.01 0.05 0.010.017 PA/FL (mm) 0.0225 0.0225 0.045 0.045 0.047 Half-life (days) 2.632.63 2.63 2.63 2.63 Rate constant, k (1/day) 0.264 0.264 0.264 0.2640.264 Vitreous vol (ml) 1.5 1.5 1.5 1.5 1.5

Table 4B shows the vitreous concentrations calculated for a 0.5 mg bolusinjection of Lucentis™ injected into the eye of a monkey using equationsdescribed herein and the half-life measured for the monkey listed inTable 4A. The first column used the measured Cmax (Gaudreault et al.)while the second used a calculated Cmax based on the dose and volume ofthe vitreous. The average concentration of Lucentis™ is about 46 ug/ml.The minimum therapeutic concentration of Lucentis™ is about 0.1 ug/mL,which may correspond to about 100% VGEF inhibition (Gaudreault et al.).Table 4B indicates that a bolus injection of 0.5 mg Lucentis™ maintainsa vitreous concentration above 0.1 ug/mL for about a month whether usingthe measured or calculated Cmax. This is consistent with monthly dosingthat has been shown to be therapeutic in clinical studies.

TABLE 4B Predicted Vitreous Predicted Vitreous Time Conc using Meas CmaxConc using Calc (days) (ug/mL) Cmax (ug/mL) 0 169.00 333.33 1 129.85256.11 2 99.76 196.77 3 76.65 151.18 4 58.89 116.16 5 45.25 89.24 634.76 68.57 7 26.71 52.68 8 20.52 40.48 9 15.77 31.10 10 12.11 23.89 119.31 18.36 12 7.15 14.10 13 5.49 10.84 14 4.22 8.33 15 3.24 6.40 16 2.494.91 17 1.91 3.78 18 1.47 2.90 19 1.13 2.23 20 0.87 1.71 21 0.67 1.32 220.51 1.01 23 0.39 0.78 24 0.30 0.60 25 0.23 0.46 26 0.18 0.35 27 0.140.27 28 0.11 0.21 29 0.08 0.16 30 0.06 0.12 31 0.05 0.09 32 0.04 0.07

Tables 4C1, 4C2, 4C3 4C4, and 4C5 show the calculated concentration ofLucentis™ in the vitreous humor for Simulation 1, Simulation 2,Simulation 3, Simulation 4, and Simulation 5 respectively. These resultsindicate Lucentis™ vitreous concentrations may be maintained above theminimum therapeutic level for about a year or more when released from adevice with porous structure characterized by PA/FL≦0.0225 mm and areservoir volume≧10 uL.

Simulation 5 corresponds to the devices used in the experiment describedin Example 8. This device had a reservoir volume of 17 uL and porousstructure characterized by PA/FL=0.047 mm. When this device is loadedwith Lucentis™, the loading dose corresponds to ⅓ of the 50 uL currentlyinjected monthly. Calculations that predict vitreous concentrationsindicate that this device with one-third of the monthly dose maymaintain Lucentis™ therapeutic concentrations for about 6 months. Whilehalf of the dose is delivered in the first month and more than 98%delivered at 6 months, therapeutic levels may still be maintained for 6months.

The ability of the device to release therapeutic agent for an extendedtime can be described by an effective device half-life. For the devicein Example 8, the effective device half-life is 29 days for delivery ofLucentis™. The device can be configured by selection of the reservoirvolume and a porous structure with an appropriate PA/FL to achieve thedesired effective half-life.

TABLE 4C1 Simulation 1 Predicted Predicted Vitreous Time Rate PredictedConc (days) (ug/day) % CR (ug/mL) 0 1.9 0.0% 4.9 10 1.9 3.8% 4.7 20 1.87.5% 4.5 30 1.7 11.0% 4.4 40 1.7 14.4% 4.2 50 1.6 17.7% 4.0 60 1.5 20.8%3.9 70 1.5 23.8% 3.7 80 1.4 26.7% 3.6 90 1.4 29.5% 3.5 100 1.3 32.2% 3.3110 1.3 34.8% 3.2 120 1.2 37.3% 3.1 130 1.2 39.7% 3.0 140 1.1 42.0% 2.9150 1.1 44.2% 2.7 160 1.0 46.3% 2.6 170 1.0 48.4% 2.5 180 1.0 50.3% 2.4190 0.9 52.2% 2.3 200 0.9 54.0% 2.3 210 0.9 55.8% 2.2 220 0.8 57.5% 2.1230 0.8 59.1% 2.0 240 0.8 60.7% 1.9 250 0.7 62.2% 1.9 260 0.7 63.6% 1.8270 0.7 65.0% 1.7 280 0.7 66.3% 1.7 290 0.6 67.6% 1.6 300 0.6 68.9% 1.5310 0.6 70.0% 1.5 320 0.6 71.2% 1.4 330 0.5 72.3% 1.4 340 0.5 73.3% 1.3350 0.5 74.4% 1.3 360 0.5 75.3% 1.2

TABLE 4C2 Simulation 2 Predicted Predicted Vitreous Time Rate PredictedConc (days) (ug/day) % CR (ug/mL) 0 1.9 0.0% 4.92 10 1.6 17.7% 4.05 201.3 32.2% 3.33 30 1.1 44.2% 2.74 40 0.9 54.0% 2.26 50 0.7 62.2% 1.86 600.6 68.9% 1.53 70 0.5 74.4% 1.26 80 0.4 78.9% 1.04 90 0.3 82.6% 0.85 1000.3 85.7% 0.70 110 0.2 88.2% 0.58 120 0.2 90.3% 0.48 130 0.2 92.0% 0.39140 0.1 93.4% 0.32 150 0.1 94.6% 0.27 160 0.1 95.5% 0.22 170 0.1 96.3%0.18 180 0.1 97.0% 0.15 190 0.0 97.5% 0.12 200 0.0 98.0% 0.10 210 0.098.3% 0.08 220 0.0 98.6% 0.07 230 0.0 98.9% 0.06 240 0.0 99.1% 0.05 2500.0 99.2% 0.04 260 0.0 99.4% 0.03 270 0.0 99.5% 0.03 280 0.0 99.6% 0.02290 0.0 99.6% 0.02 300 0.0 99.7% 0.01 310 0.0 99.8% 0.01 320 0.0 99.8%0.01 330 0.0 99.8% 0.01 340 0.0 99.9% 0.01 350 0.0 99.9% 0.01 360 0.099.9% 0.00

TABLE 4C3 Simulation 3 Predicted Predicted Vitreous Time Rate PredictedConc (days) (ug/day) % CR (ug/mL) 0 3.9 0.0% 9.8 10 3.6 7.5% 9.1 20 3.314.4% 8.4 30 3.1 20.8% 7.8 40 2.8 26.7% 7.2 50 2.6 32.2% 6.7 60 2.437.3% 6.2 70 2.3 42.0% 5.7 80 2.1 46.3% 5.3 90 1.9 50.3% 4.9 100 1.854.0% 4.5 110 1.7 57.5% 4.2 120 1.5 60.7% 3.9 130 1.4 63.6% 3.6 140 1.366.3% 3.3 150 1.2 68.9% 3.1 160 1.1 71.2% 2.8 170 1.0 73.3% 2.6 180 1.075.3% 2.4 190 0.9 77.2% 2.2 200 0.8 78.9% 2.1 210 0.8 80.5% 1.9 220 0.781.9% 1.8 230 0.7 83.3% 1.6 240 0.6 84.5% 1.5 250 0.6 85.7% 1.4 260 0.586.8% 1.3 270 0.5 87.7% 1.2 280 0.4 88.7% 1.1 290 0.4 89.5% 1.0 300 0.490.3% 1.0 310 0.3 91.0% 0.9 320 0.3 91.7% 0.8 330 0.3 92.3% 0.8 340 0.392.9% 0.7 350 0.3 93.4% 0.6 360 0.2 93.9% 0.6

TABLE 4C4 Simulation 4 Predicted Predicted Vitreous Time Rate PredictedConc (days) (ug/day) % CR (ug/mL) 0 3.89 0.0% 9.83 10 2.64 32.2% 6.67 201.79 54.0% 4.52 30 1.21 68.9% 3.06 40 0.82 78.9% 2.08 50 0.56 85.7% 1.4160 0.38 90.3% 0.95 70 0.26 93.4% 0.65 80 0.17 95.5% 0.44 90 0.12 97.0%0.30 100 0.08 98.0% 0.20 110 0.05 98.6% 0.14 120 0.04 99.1% 0.09 1300.02 99.4% 0.06 140 0.02 99.6% 0.04 150 0.01 99.7% 0.03 160 0.01 99.8%0.02 170 0.01 99.9% 0.01 180 0.00 99.9% 0.01 190 0.00 99.9% 0.01 2000.00 100.0% 0.00 210 0.00 100.0% 0.00 220 0.00 100.0% 0.00 230 0.00100.0% 0.00 240 0.00 100.0% 0.00 250 0.00 100.0% 0.00 260 0.00 100.0%0.00 270 0.00 100.0% 0.00 280 0.00 100.0% 0.00 290 0.00 100.0% 0.00 3000.00 100.0% 0.00 310 0.00 100.0% 0.00 320 0.00 100.0% 0.00 330 0.00100.0% 0.00 340 0.00 100.0% 0.00 350 0.00 100.0% 0.00 360 0.00 100.0%0.00

TABLE 4C5 Simulation 5 Predicted Predicted Vitreous Time Rate PredictedConc (days) (ug/day) % CR (ug/mL) 0 4.1 0.0% 10.27 10 3.2 21.2% 8.09 202.5 38.0% 6.37 30 2.0 51.2% 5.02 40 1.6 61.5% 3.95 50 1.2 69.7% 3.11 601.0 76.1% 2.45 70 0.8 81.2% 1.93 80 0.6 85.2% 1.52 90 0.5 88.3% 1.20 1000.4 90.8% 0.94 110 0.3 92.8% 0.74 120 0.2 94.3% 0.58 130 0.2 95.5% 0.46140 0.1 96.5% 0.36 150 0.1 97.2% 0.29 160 0.1 97.8% 0.22 170 0.1 98.3%0.18 180 0.1 98.6% 0.14 190 0.0 98.9% 0.11 200 0.0 99.2% 0.09 210 0.099.3% 0.07 220 0.0 99.5% 0.05 230 0.0 99.6% 0.04 240 0.0 99.7% 0.03 2500.0 99.7% 0.03 260 0.0 99.8% 0.02 270 0.0 99.8% 0.02 280 0.0 99.9% 0.01290 0.0 99.9% 0.01 300 0.0 99.9% 0.01 310 0.0 99.9% 0.01 320 0.0 100.0%0.00 330 0.0 100.0% 0.00 340 0.0 100.0% 0.00 350 0.0 100.0% 0.00 360 0.0100.0% 0.00

Z. Yao et al. (Prevention of Laser Photocoagulation Induced ChoroidalNeovascularization Lesions by Intravitreal Doses of Ranibizumab inCynomolgus Monkeys, ARVO 2009 abstract D906) have performed apreclinical study to determine the lowest efficacious Lucentis™ dose incynomolgus monkeys that leads to 100% prevention of laserphotocoagulation treatment-induced Grade IV choroidal neovascularization(CNV) lesions.™ This model has been shown to be relevant to AMD.Intravitreal injection of Lucentis™ at all doses tested completelyinhibited the development of Grade IV CNV lesions. Table 4D showspredictions of Lucentis™ vitreous concentrations for the lowest totalamount of Lucentis™ investigated (intravitreal injection of 5 ug on days1, 6, 11, 16, 21 and 26), using the equations described herein andpharmacokinetic parameters listed in Table 4A. This data indicates thatit is not necessary to achieve the high Cmax of a 0.5 mg single bolusinjection in order to be therapeutic.

FIG. 19A compares this predicted profile with that predicted for thedevice in Example 8. This data further supports that the release profilefrom a device in accordance with embodiments of the present inventionmay be therapeutic for at least about 6 months. The single injection of500 ug corresponds to a 50 uL bolus injection of Lucentis™ that cangiven at monthly intervals, and the range of therapeutic concentrationsof Lucentis™ (ranibizumab) in the vitreous extends from about 100 ug/mLto the minimum inhibitory (therapeutic) concentration of about 0.1 ug/mLat about 1 month, for example. The minimum inhibitory concentrationcorresponding to the lower end of the range of therapeuticconcentrations in the vitreous humor can be determined empirically byone of ordinary skill in the art in accordance with the examplesdescribed herein. For example, a lose does study of a series of sixLucentis™ injections, 5 ug each, can be administered so as to provide aconcentration in the vitreous of at least about 1 ug/mL, and thetherapeutic benefit of the injections assessed as described herein.

TABLE 4D Predicted Lucentis Time Vitreous Conc (days) (ug/mL) 0 0.00 13.33 2 2.56 3 1.97 4 1.51 5 1.16 6 4.23 7 3.25 8 2.49 9 1.92 10 1.47 114.46 12 3.43 13 2.64 14 2.02 15 1.56 16 4.53 17 3.48 18 2.67 19 2.05 201.58 21 4.55 22 3.49 23 2.68 24 2.06 25 1.58 26 4.55 27 3.50 28 2.69 292.06 30 1.59 35 0.42 40 0.11 45 0.03 50 0.01 60 0.00 70 0.00 80 0.00 900.00

The concentration profiles of a therapeutic agent comprising Lucentis™were determined as shown below based on the teachings described hereinand with drug half-life of nine days for Lucentis™ in the human eye. Theexamples shown below for injections of the commercially availableformulation Lucentis™ and the nine day half life show unexpectedresults, and that a volume of formulation corresponding to a montlybolus injection into the device as described herein can providetherapeutic benefit for at least about two months. The device volume andthe porous structure can be be tuned to receive the predetermined volumeof formulation and provide sustained rease for an extended time.Additonal tuning of the device can include the half-life of thetherapeutic agent in the eye, for example nine days for Lucentis™, andthe minmimum inhibitory concentration of the therapeutic agent asdetermined based on the teachings as described herein.

FIG. 19B shows determined concentrations of Lucentis™ in the vitreoushumor for a first 50 uL injection into a 25 uL device and a second 50 uLinjection at 90 days. The calculations show that the 50 uL dosage of themonthly FDA approved bolus injection can be used to treat the eye forabout 90 days, and that the injections can be repeated to treat the eye,for example at approximately 90 day intervals. The Lucentis™ maycomprise a predetermined amount of the commercially availableformulation injected into the device. The commercially availableformulation of Lucentis™ has a concentration of ranibizumab of 10 mg/mL,although other concentrations can be used for example as describedherein below with reference to a 40 mg/mL solution of injectedranibizumab. The predetermine amount corresponds to the amount of themonthly bolus injection, for example 50 uL. The therapeutic device maycomprise a substantially fixed volume container reservoir having avolume of 25 uL, such that a first 25 uL portion of the 50 uL injectionis contained in the reservoir for sustained and/or controlled releaseand a second 25 uL portion of the 50 uL injection is passed through theporous structure and released into the vitreous with a 25 uL bolus. Thefilling efficiency of the injection into the device may comprise lessthan 100%, and the reservoir volume and injection volume can be adjustedbased on the filling efficiency in accordance with the teachingsdescribed herein. For example, the filling efficiency may compriseapproximately 90%, such that the first portion comprises approximately22.5 uL contained in the chamber of the container reservoir and thesecond portion comprises approximately 27.5 uL passed through the devicefor the 50 uL injected into the therapeutic device. The initialconcentration of Lucentis™ in the vitreous humor corresponds to about 60ug/mL immediately following injection into the reservoir device. Theconcentration of Lucentis™ in the vitreous humor decreases to about 3.2ug/mL at 90 days. A second 50 uL injection of Lucentis™ approximately 90days after the first injection increases the concentration to about 63ug/mL. The concentration of Lucentis™ in the vitreous humor decreases toabout 3.2 ug/mL at 180 days after the first injection and 90 days afterthe second injection. These calculations show that the concentration ofLucentis™ can be continuously maintained above a minimum inhibitoryconcentration of about 3 ug per ml with the 50 uL injection into thedevice. Additional injections can be made, for example every 90 days forseveral years to deliver the therapeutic agent to treat the patient.

FIG. 19C shows determined concentrations of Lucentis™ in the vitreoushumor for a first 50 uL injection into a 32 uL device and a second 50 uLinjection at a time greater than 90 days. The calculations show that the50 uL dosage of the monthly FDA approved bolus injection can be used totreat the eye for about 90 days, and that the injections can be repeatedto treat the eye, for example at approximately 90 day intervals. TheLucentis™ may comprise a predetermined amount of the commerciallyavailable formulation injected into the device. The predetermine amountcorresponds to the amount of the monthly bolus injection, for example 50uL. The therapeutic device may comprise a substantially fixed volumecontainer reservoir having a volume of 32 uL, such that a first 32 uLportion of the 50 uL injection is contained in the reservoir forsustained and/or controlled release and a second 18 uL portion of the 50uL injection is passed through the porous structure and released intothe vitreous with an 18 uL bolus. The filling efficiency of theinjection into the device may comprise less than 100%, and the reservoirvolume and injection volume can be adjusted based on the fillingefficiency in accordance with the teachings described herein. Forexample, the filling efficiency may comprise approximately 90%, suchthat the first portion comprises approximately 29 uL contained in thechamber of the reservoir container and the second portion comprisesapproximately 21 uL passed through the device for the 50 uL of Lucentis™injected into the therapeutic device. The initial concentration ofLucentis™ in the vitreous humor corresponds to about 45 ug/mLimmediately following injection into the reservoir device. Theconcentration of Lucentis™ in the vitreous humor decreases to about 4ug/mL at 90 days. A second 50 uL injection of Lucentis™ approximately 90days after the first injection increases the concentration to about 50ug/mL. The concentration of Lucentis™ in the vitreous humor decreases toabout 4 ug/mL at 180 days after the first injection and 90 days afterthe second injection. These calculations show that the concentration ofLucentis™ can be continuously maintained above a minimum inhibitoryconcentration of about 4 ug per ml with the 50 uL injection into thedevice. Additional injections can be made every 120 days for severalyears to deliver the therapeutic agent to treat the patient. Theinjections can be made more frequently or less frequently, dependingupon the minimum inhibitory concentration, the release rate profile, andthe discretion of the treating physician.

FIG. 19D shows determined concentrations of Lucentis™ in the vitreoushumor for a first 50 uL injection into a 50 uL device and a second 50 uLinjection at 90 days. The calculations show that the 50 uL dosage of themonthly FDA approved bolus injection can be used to treat the eye forabout 90 days, and that the injections can be repeated to treat the eye,for example at approximately 90 day intervals. The Lucentis™ maycomprise a predetermined amount of the commercially availableformulation injected into the device. The filling efficiency of theinjection into the device may comprise less than 100%, and the reservoirvolume and injection volume can be adjusted based on the fillingefficiency in accordance with the teachings described herein. Forexample, the filling efficiency may comprise approximately 90%, suchthat the first portion comprises approximately 45 uL contained in thechamber of the reservoir container and the second portion comprisesapproximately 5 uL passed through the device for the 50 uL of Lucentis™injected into the therapeutic device. The initial concentration ofLucentis™ in the vitreous humor corresponds to about 11 ug/mLimmediately following injection into the reservoir device. Theconcentration of Lucentis™ in the vitreous humor decreases to about 5.8ug/mL at 90 days. A second 50 uL injection of Lucentis™ approximately 90days after the first injection increases the concentration to about 17ug/mL. The concentration of Lucentis™ in the vitreous humor decreases toabout 5.8 ug/mL at 180 days after the first injection and 90 days afterthe second injection. These calculations show that the concentration ofLucentis™ can be continuously maintained above a minimum inhibitoryconcentration of about 5 ug per ml with the 50 uL injection into thedevice. Additional injections can be made, for example every 90 days forseveral years to deliver the therapeutic agent to treat the patient.

FIG. 19E shows determined concentrations of Lucentis™ in the vitreoushumor for a first 50 uL injection into a 50 uL device and a second 50 uLinjection at 90 days. The calculations show that the 50 uL dosage of themonthly FDA approved bolus injection can be used to treat the eye forabout 130 days, and that the injections can be repeated to treat theeye, for example at approximately 120 day intervals. The Lucentis™ maycomprise a predetermined amount of the commercially availableformulation injected into the device. The filling efficiency of theinjection into the device may comprise less than 100%, and the reservoirvolume and injection volume can be adjusted based on the fillingefficiency in accordance with the teachings described herein. Forexample, the filling efficiency may comprise approximately 90%, suchthat the first portion comprises approximately 45 uL contained in thechamber of the reservoir container and the second portion comprisesapproximately 5 uL passed through the device for the 50 uL of Lucentis™injected into the therapeutic device. The initial concentration ofLucentis™ in the vitreous humor corresponds to about 11 ug/mLimmediately following injection into the reservoir device. Theconcentration of Lucentis™ in the vitreous humor decreases to about 4ug/mL at 133 days. A second 50 uL injection of Lucentis™ approximately130 days after the first injection increases the concentration to about15 ug/mL. Based on these calculations, the concentration of Lucentis™ inthe vitreous humor decreases to about 4 ug/mL at 266 days after thefirst injection and 90 days after the second injection. Thesecalculations show that the concentration of Lucentis™ can becontinuously maintained above a minimum inhibitory concentration ofabout 4 ug per ml with the 50 uL injection into the device. Additionalinjections can be made, for example every 90 days for several years todeliver the therapeutic agent to treat the patient.

Although FIGS. 19B to 19P make reference to injections of commerciallyavailable off the shelf formulations of Lucentis™, therapeutic device100 can be similarly configured to release many formulations of thetherapeutic agents as described herein, for example with reference toTable 1A and the Orange Book of FDA approved formulations and similarbooks of approved drugs in many countries, unions and jurisdictions suchas the European Union. For example, based on the teachings describedherein, one can determine empirically the parameters of therapeuticdevice 100 so as to tune the device to receive a injection of acommercially available formulation corresponding to a monthly bolusinjections and release the injected therapeutic agent with amounts abovethe minimum inhibitory concentration for an extended time of at leastabout two months, for example, at least about three months, for example,or about four months, for example.

FIG. 19F shows determined concentrations of ranibizumab in the vitreoushumor for a 50 uL Lucentis™ injection into a 50 uL device having arelease rate index of 0.05. The concentration of ranibizumab in thevitreous humor peaks at around 9 ug/mL and is at or above 4 ug/mL forabout 145 days. The concentration remains above about 1 ug/mL for about300 days. The concentration is about 0.6 ug/mL at 360 days, and can besuitable for treatment with a single injection up to one year, based ona minimum inhibitory concentration of about 0.5. The minimum inhibitoryconcentration can be determined empirically by a person of ordinaryskill in the art based on the teachings described herein.

FIG. 19G shows determined concentrations of ranibizumab in the vitreoushumor for a 50 uL Lucentis™ injection into a 75 uL device having arelease rate index of 0.05. The concentration of ranibizumab in thevitreous humor peaks at around 6.5 ug/mL and is at or above 4 ug/mL forabout 140 days. The concentration remains above about 1 ug/mL for about360 days.

FIG. 19H shows determined concentrations of ranibizumab in the vitreoushumor for a 50 uL Lucentis™ injection into a 100 uL device having arelease rate index of 0.05. The concentration of ranibizumab in thevitreous humor peaks at around 5 ug/mL and is at or above 4 ug/mL forabout 116 days. The concentration remains above about 1 ug/mL for morethan 360 days and is about 1.5 ug/mL at 360 days.

FIG. 19I shows determined concentrations of ranibizumab in the vitreoushumor for a 50 uL Lucentis™ injection into a 125 uL device having arelease rate index of 0.05. The concentration of ranibizumab in thevitreous humor peaks at around 4.3 ug/mL and does not equal or exceed 4ug/mL. The concentration remains above about 1 ug/mL for more than 360days and is about 1.5 ug/mL at 360 days.

FIG. 19J shows determined concentrations of ranibizumab in the vitreoushumor for a 50 uL Lucentis™ injection into a 150 uL device having arelease rate index of 0.05. The concentration of ranibizumab in thevitreous humor peaks at around 3.5 ug/mL and does not equal or exceed 4ug/mL. The concentration remains above about 1 ug/mL for more than 360days and is about 1.5 ug/mL at 360 days.

FIG. 19K shows determined concentrations of ranibizumab in the vitreoushumor for a 50 uL Lucentis™ injection into a 100 uL device having arelease rate index of 0.1. These determined concentrations are similarto the determined concentrations of FIG. 19F, and show that the releaserate index of the porous structure can be tuned with the device volumeto provide therapeutic concentration profile for an extended time. Forexample, by doubling the volume of the reservoir so as to half theconcentration of therapeutic agent in the vitreous, the release rateindex can be doubled so as to provide a similar therapeuticconcentration profile. The concentration of ranibizumab in the vitreoushumor peaks at around 9 ug/mL and is at or above 4 ug/mL for about 145days. The concentration remains above about 1 ug/mL for about 300 days.The concentration is about 0.6 ug/mL at 360 days.

FIGS. 19L to 19P show examples of release rate profiles with 125 uLreservoir devices having the RRI vary from about 0.065 to about 0.105,such that these devices are tuned to receive the 50 uL injection ofLucentis™ and provide sustained release above a minimum inhibitoryconcentration for at least about 180 days. These calculations used adrug half life in the vitreous of 9 days to determine the profiles and100% efficiency of the injection.

FIG. 19L shows determined concentration profiles of ranibizumab in thevitreous humor for a 50 uL Lucentis™ injection into a 125 uL reservoirdevice having a release rate index of 0.105. The concentration ofranibizumab in the vitreous at 180 days is about 3.128 ug/mL.

FIG. 19M shows determined concentration profiles of ranibizumab in thevitreous humor for a 50 uL Lucentis™ injection into a 125 uL reservoirdevice having a release rate index of 0.095. The concentration ofranibizumab in the vitreous at 180 days is about 3.174 ug/mL.

FIG. 19N shows determined concentration profiles of ranibizumab in thevitreous humor for a 50 uL Lucentis™ injection into a 125 uL reservoirdevice having a release rate index of 0.085. The concentration ofranibizumab in the vitreous at 180 days is about 3.185 ug/mL.

FIG. 19O shows determined concentration profiles of ranibizumab in thevitreous humor for a 50 uL Lucentis™ injection into a 125 uL reservoirdevice having a release rate index of 0.075. The concentration ofranibizumab in the vitreous at 180 days is about 3.152 ug/mL.

FIG. 19P shows determined concentration profiles of ranibizumab in thevitreous humor for a 50 uL Lucentis™ injection into a 125 uL reservoirdevice having a release rate index of 0.065. The concentration ofranibizumab in the vitreous at 180 days is about 3.065 ug/mL.

The optimal RRI for the concentration of ranibizumab at 180 days for areservoir volume of 125 uL and a 50 uL injection of Lucentis™ can becalculated based on the equations as described herein, and is about0.085. Although the optimal value is 0.085, the above graphs show thatthe reservoir and release rate index can be tuned to provide therapeuticamounts of ranibizumab above a minimum inhibitory concentration of 3ug/mL with many values of the RRI and reservoir volume, for examplevalues within about +/−30% to +/−50% of the optimal values for thepredetermined quantity of Lucentis™ formulation.

Table 4E shows values of parameters used to determine the ranibizumabconcentration profiles as in FIGS. 19K to 19P.

TABLE 4E Diffusion coeff (cm2/s) 1.0E−06 Initial Loading (ug/mL) 10000Reservoir Vol (ml) 0.125 PA/TL (mm) varied Half-life (days) 9 Rateconstant, k (1/day) 0.077 Vitreous vol (ml) 4.5 Volume injected (mL)0.05 Time step (days) 0.1 Time between refills (days) 180 RefillEfficiency 100%

The therapeutic concentration profiles of examples of FIGS. 19B to 19Pwere determined with a nine day half-life of the drug in the vitreoushumor of the human eye. The therapeutic concentration profiles can bescaled in accordance with the half life of the therapeutic agent in theeye. For example, with an eighteen day half life, the concentration inthese examples will be approximately twice the values shown in the graphat the extended times, and with a 4.5 day half-life, the concentrationswill be approximately half the values shown with the extended times. Asan example, a drug half life of eighteen days instead of nine days willcorrespond to a concentration of about 1.4 ug/mL at 360 days instead ofabout 0.6 ug/mL as shown in FIGS. 19F and 19K. This scaling of theconcentration profile based on drug half life in the vitreous can beused to tune the volume and sustained release structures of thetherapeutic device, for example in combination with the minimuminhibitory concentration. Although the above examples were calculatedfor Lucentis™, similar calculations can be performed for therapeuticagents and formulations as described herein, for example as describedherein with reference to Table 1A.

Based on the teachings described herein, a person of ordinary skill inthe art can determine the release rate index and volume of thetherapeutic agent based on the volume of formulation injected into thedevice and minimum inhibitory concentration. This tuning of the devicevolume and release rate index based on the volume of formulationinjected can produce unexpected results. For example, with a clinicallybeneficial minimum inhibitory concentration of about 4 ug/mL, a singlebolus injection corresponding to a one month injection can provide atherapeutic benefit for an unexpected three or more months, such as fourmonths. Also, for a clinically beneficial minimum inhibitoryconcentration of at least about 1.5 ug/mL, a single bolus injectioncorresponding to a one month injection can provide a therapeutic benefitfor an unexpected twelve or more months. The clinically beneficialminimum inhibitory concentration can be determined empirically based onclinical studies as described herein.

Although the examples of FIGS. 19F to 19K assumed a filling efficiencyof one hundred percent, a person of ordinary skill in the art based onthe teachings as described herein can determine the release rateprofiles for filling efficiencies less than 100%, for example with 90%filling efficiency as shown above. Such filling efficiencies can beachieved with injector apparatus and needles as described herein, forexample with reference to FIGS. 7, 7A, 7A1 and 7A2.

FIG. 19Q shows determined concentrations of ranibizumab in the vitreoushumor for a 10 uL concentrated Lucentis™ (40 mg/mL) injection into a 10uL device having a release rate index of 0.01 and in which theranibizumab has a half life in the vitreous humor of about nine days.These data show that an injection of 10 uL of concentrated (40 mg/mL)Lucentis™ into a 10 uL reservoir device can maintain the concentrationof Lucentis™ above at least about 2 ug/mL for at least about 180 dayswhen the half life of Lucentis™ in the vitreous is at least about ninedays, and that the device can provide therapeutic concentrations for anextended time of at least about 180 days when the minimum inhibitoryconcentration comprises no more than about 2 ug/mL.

FIG. 19R shows determined concentrations of ranibizumab in the vitreoushumor for a 10 uL concentrated Lucentis™ (40 mg/mL) injection into a 10uL device having a release rate index of 0.01 and in which theranibizumab has a half life in the vitreous humor of about five days.These data show that an injection of 10 uL of concentrated (40 mg/mL)Lucentis™ into a 10 uL reservoir device can maintain the concentrationof Lucentis™ above at least about 1 ug/mL for at least about 180 dayswhen the half life of Lucentis™ in the vitreous is at least about fivedays, and that the device can provide therapeutic concentrations for anextended time of at least about 180 days when the minimum inhibitoryconcentration comprises no more than about 1 ug/mL.

FIG. 19S shows determined concentrations of ranibizumab in the vitreoushumor for a 10 uL standard Lucentis™ (10 mg/mL) injection into a 10 uLdevice having a release rate index of 0.01 and in which the ranibizumabhas a half life in the vitreous humor of about nine days. These datashow that an injection of 10 uL of standard commercially available (10mg/mL) Lucentis™ into a 10 uL reservoir device can maintain theconcentration of Lucentis™ above at least about 0.5 ug/mL for at leastabout 180 days when the half life of Lucentis™ in the vitreous is atleast about nine days, and that the device can provide therapeuticconcentrations for an extended time of at least about 180 days when theminimum inhibitory concentration comprises no more than about 0.5 ug/mL.

FIG. 19T shows determined concentrations of ranibizumab in the vitreoushumor for a 10 uL standard Lucentis™ (10 mg/mL) injection into a 10 uLdevice having a release rate index of 0.01 and in which the ranibizumabhas a half life in the vitreous humor of about five days. These datashow that an injection of 10 uL of standard commercially available (10mg/mL) Lucentis™ into a 10 uL reservoir device can maintain theconcentration of Lucentis™ above at least about 0.25 ug/mL for at leastabout 180 days when the half life of Lucentis™ in the vitreous is atleast about five days, and that the device can provide therapeuticconcentrations for an extended time of at least about 180 days when theminimum inhibitory concentration comprises no more than about 0.25ug/mL.

Example 10 Calculations of Target Device Characteristics for a DeviceReleasing Drug from a Suspension

Triamcinolone acetonide is a corticosteroid used to treat uveitis andother diseases involving ocular inflammation. A 4 mg intravitrealinjection of a suspension of triamcinolone acetonide may be administeredto patients unresponsive to topical corticosteroids. Calculations asdescribed herein were performed to determine the characteristics of adevice that would release therapeutic amounts for an extended period oftime.

Consider a device with 10 uL reservoir volume loaded with 0.4 mg using acommercial drug product (40 mg/mL triamcinolone acetonide). Calculationswere performed using a value of 19 ug/mL for the solubility oftriamcinolone acetonide measured at 37° C. in 0.2 M potassium chlorideand a diffusion coefficient of 5 e-6 cm²/s representative of a smallmolecule. The target release rate is 1 ug/day based upon publishedclinical data. As an example, consider the 0.2 media grade stainlesssteel characterized in Example 8 with P/F=0.12 and a thickness of 0.5mm. Using these values, the calculations suggest that therapeuticrelease rates could be achieved with a device containing a porouscylinder with an area of 5 mm². This could be achieved with acylindrical device having an inner diameter of 2 mm and a length ofporous tubing of 1 mm. Alternatively, the end of the device could be aporous cup with height of 0.8 mm (0.5 mm thick porous face plus 0.3 mmlength) of porous tubing.

Assuming a typical value of 3 hours for the half-life of a smallmolecule in the vitreous, these calculations suggest the device willachieve a steady state triamcinolone acetonide vitreous concentration of0.12 ug/mL.

Example 11 Calculation of Release Rate Profile for a Therapeutic AgentSuspension Disposed in the Reservoir and Released through the PorousFrit Structure

FIG. 20 shows a calculated time release profile of a therapeutic agentsuspension in a reservoir as in Example 10. Triamcinolone Acetonideconcentrations in human vitreous were determined for a 10 uL device withRRI of 1.2 mm and shown. The calculations were based on the equationsshown above for the suspension. The profile was generated with numericalsimulation. Assuming a constant delivery rate of 1 ug/day startinginstantaneously at T=0, the concentration in the vitreous of a human eyecan reach within 99% of the steady state value in 1 day. At the otherend of the drug release profile, the simulation shows the vitreousconcentration when substantially all of the solid drug is gone; morethan 99% of the dissolved drug is delivered within a day.

Assuming a typical value of 3 hours for the half-life of a smallmolecule in the vitreous, these calculations indicate that the devicewill achieve a substantially steady state triamcinolone acetonidevitreous concentration of 0.12 ug/mL in the rabbit or monkey (vitreousvolume of 1.5 mL) or 0.04 ug/mL in the human eye (vitreous volume of 4.5mL). The steady state vitreous concentration are maintained until thereis no longer solid triamcinolone acetonide of the suspension in thereservoir. As shown in FIG. 20, a device with a 10 uL reservoir volumeand Release Rate Index of 1.2 mm can produce substantially constant drugconcentration amounts in the human vitreous for approx. 400 days.Additional experimental and clinical studies based on the teachingsdescribed herein can be conducted to determine the release rate profilein situ in human patients, and the drug reservoir volume and releaserate index configured appropriately for therapeutic benefit for a targettime of drug release. The substantially constant drug concentrationamounts can provide substantial therapy and decrease side effects.Similar studies can be conducted with many suspensions of manytherapeutic agents as described herein, for example suspensions ofcorticosteroids and analogues thereof as described herein.

Example 12 Measured of Release Rate Profiles for Avastin™ through thePorous Frit Structures Coupled to Reservoirs of Different Sizes andDependence of Release Rate Profile on Reservoir Size

FIG. 21 shows a release rate profiles of therapeutic devices comprisingsubstantially similar porous frit structures and a 16 uL reservoir and a33 uL reservoir. The release rate index of each frit was approximately0.02. The release rate for two therapeutic devices each comprising a 16uL reservoir and two therapeutic devices each comprising a 33 uLreservoir are shown. The device comprising the 33 uL reservoir releasedthe Avastin™ at approximately twice the rate of the device comprising 16uL reservoir. These measured data show that the release rate index andreservoir size can determine the release rate profile, such that therelease rate index and reservoir can be configured to release thetherapeutic agent for an extended time.

First Study: The data were measured with a 16 uL volume reservoir asfollows: 25 mg/mL Avastin™; Frit #2 (0.031×0.049″, media grade 0.2 um,316L SS, Mott Corporation); Substantially similar materials as Example 8above (Teflon heat shrink tubing and silicone septum); 37 C; Data istruncated when one of two replicates formed a bubble. See data in Table5A below.

Second Study: The data were measured with a 33 uL reservoir as follows:25 mg/mL Avastin™; Frit #2 (0.031×0.049″, media grade 0.2 um, 316L SS,Mott Corporation); Machined from solid beading, closed with a metal rod;37 C; Data is truncated when one of two replicates formed a bubble.

TABLE 5A Measured Release of Avastin ™ and RRI. Volume (uL) Device RRI(mm) SS (ug/day)2 33 1 0.015 0.35 33 2 0.018 0.16 16 1 0.018 0.05 16 20.022 0.06 Mean 0.018 % CV 16%

SS is the average of the squared difference between predicted andmeasured rates, and % CV refers to the coefficient of variation, a knownstatistical parameter.

Example 13 Measured Release Rate Profiles for Avastin™ Through thePorous Frit Structures

FIG. 22A shows cumulative release for Avastin™ with porous fritstructures having a thickness of 0.049″. The experiments used: 25 mg/mLAvastin™; Frit #2 (0.031×0.049″, media grade 0.2 um, 316L SS, MottCorporation); Machined polycarbonate surrogate with screw; ReservoirVolume 37 uL; 37 C. The device number and corresponding RRI's for eachtested device are listed in Table 5B below. The determined RRI based onmeasurements is 0.02, consistent with the model for release of thetherapeutic agent as described herein. Although some variability isnoted with regards to the measured RRI for each test device, the RRI foreach device can be used to determine the release of the therapeuticagent, and the porous structure can be further characterized with gasflow as described herein to determine the RRI prior to placement in thepatient.

TABLE 5B Device RRI (mm) SS (ug/day)2  1 0.029 26.0  2 0.027 8.5  50.018 3.7 30 0.013 0.1 31 0.013 0.1 32 0.015 0.7 33 0.022 30.5 Mean0.020 % CV 34%

FIG. 22B1 shows cumulative release for Avastin™ with porous fritstructures having a thickness of 0.029″. The experiments used: 25 mg/mLAvastin™; Frit #3 (0.038×0.029″, media grade 0.2 um, 316L SS, MottCorporation); Machined polycarbonate surrogate with screw; ReservoirVolume 37 uL; 37 C. The device number and corresponding RRI's for eachtested device are listed in Table 5C below. The determined RRI based onmeasurements is 0.034, consistent with the model for release of thetherapeutic agent as described herein. Although some variability isnoted with regards to the measured RRI for each test device, the RRI foreach device can be used to determine the release of the therapeuticagent, and the porous structure can be further characterized with gasflow as described herein to determine the RRI prior to placement in thepatient.

TABLE 5C Device RRI (mm) SS (ug/day)2  9 0.033 0.7 10 0.044 10.8 130.030 0.7 27 0.043 15.8 28 0.033 2.6 34 0.030 0.9 35 0.027 0.3 36 0.0345.5 Mean 0.034 % CV 19%

Table 5D shows an update to Table 5B showing experimental results for upto 130 days. Similarly, Table 5E is an update to Table 5C. In bothcases, the RRI was determined by fitting the rate data from each device.For the analysis of data up to 130 days, the first data point isexcluded from the fit because the model assumes the maximum deliveryrate occurs at time zero while there is some startup time oftenassociated with measured release profiles. The startup time may berelated to the time it takes to displace all of the air in the frit. Useof different techniques to displace the air in the frit may reduce thestartup time.

This early data has some noise that appears to be related toexperimental issues such as contamination from excess protein that ispresent on the screw from filling the device and was not completelyrinsed off at the start of the experiment. The contamination appears tooccur randomly as receiver liquid may rinse off the protein whiletransferring the device from vial to vial at some timepoints but notothers. A more accurate assessment of RRI can be obtained by usingdevices that had fewer or no outliers, as indicated by low values of SS.When this is done, the RRIs from Table 5D and 5E are 0.014 and 0.030 mm,respectively. Similar values for RRI are obtained from data up to 45days and data up to 130 days, supporting the validity of the model.

TABLE 5D Up to 45 Days Up to 130 Days SS SS Device RRI (mm)(ug/day){circumflex over ( )}2 RRI (mm) (ug/day){circumflex over ( )}2 1 0.029 26.0 0.032 13.7  2 0.027 8.5 0.028 5.5  5 0.018 3.7 0.014 1.730 0.013 0.1 0.021 4.8 31 0.013 0.1 0.022 9.3 32 0.015 0.7 0.023 3.4 330.022 30.5 0.028 16.4 Mean 0.020 0.024 % CV 34% 24% Mean for 0.014 0.014SS < 2

TABLE 5E Up to 45 Days Up to 130 Days SS SS Device RRI (mm)(ug/day){circumflex over ( )}2 RRI (mm) (ug/day){circumflex over ( )}2 9 0.033 0.7 0.034 4.4 10 0.044 10.8 0.034 2.0 13 0.030 0.7 0.044 11.627 0.043 15.8 0.045 6.8 28 0.033 2.6 0.031 0.5 34 0.030 0.9 0.030 0.7 350.027 0.3 0.029 1.3 36 0.034 5.5 0.034 5.9 Mean 0.034 0.035 % CV 19% 17%Mean for 0.030 0.030 SS < 2

FIG. 22B2 shows rate of release for Avastin™ with porous frit structureshaving a thickness of 0.029″ as in FIG. 22B1. The rate of release can bedetermined from the measurements and the cumulative release. Theoutliers in this data can be related to measurement error, such ascontamination that provides a signal in the mBCA protein assay.

FIG. 23A shows cumulative release for Avastin™ with a reservoir volumeof 20 uL. The experiment used: 25 mg/mL Avastin™; Frit #6 (0.038×0.029″,media grade 0.2 um, 316L SS, Mott Corporation); Machined polycarbonatesurrogate with screw; 37 C. The determined RRI based on measurements is0.05 mm, consistent with the model for release of the therapeutic agentas described herein.

FIG. 23A-1 shows cumulative release to about 90 days for Avastin™ with areservoir volume of 20 uL as in FIG. 23A. The RRI of 0.053 mmcorresponds substantially to the RRI of 0.05 of FIG. 23 and demonstratesstability of the release of therapeutic agent through the porousstructure.

FIG. 23B shows rate of release as in FIG. 23A. The release rate datashow a rate of release from about 5 ug per day to about 8 ug per day.Although the initial release rate at the first day is slightly lowerthan subsequent rates, the rate of release is sufficiently high toprovide therapeutic effect in accordance with the drug release model.Although there can be an initial period of about a few days for therelease rate profile to develop, possibly related to wetting of theinterconnecting channels of the porous structure, the release rateprofile corresponds substantially to the release rate index (RRI) of0.05. Based on the teachings described herein, a person of ordinaryskill in the art could determine the release rate profile withadditional data for an extended time of at least about one month, forexample at least about three months, six months or more, so as todetermine the release rate profile for an extended time.

FIG. 23B-1 shows rate of release as in FIG. 23A-1.

FIG. 24A shows cumulative release for Avastin™ with a 0.1 media gradeporous frit structure. This experiment used: 25 mg/mL Avastin™; Frit #5(0.038×0.029″, media grade 0.1 um, 316L SS, Mott Corporation); Machinedpolycarbonate surrogate with screw; Reservoir Volume 20 uL; 37 C. Thedetermined RRI based on measurements is 0.03, consistent with the modelfor release of the therapeutic agent as described herein.

FIG. 24A-1 shows cumulative to about 90 days release for Avastin™ with a0.1 media grade porous frit structure as in FIG. 24A. The release rateof 0.038 mm corresponds substantially to the relase rate of 0.03 of FIG.24A and demonstrates the stability of release of the therapeutic agentthrough the porous structure.

FIG. 24B shows rate of release as in FIG. 24A. The release rate datashow a rate of release from about 2 ug per day to about 6 ug per day.Although the initial release rate at the first day is slightly lowerthan subsequent rates, the rate of release is sufficiently high toprovide therapeutic effect in accordance with the drug release model.Although there can be an initial period of a few days for the releaserate profile to develop, possibly related to wetting of theinterconnecting channels of the porous structure, the release rateprofile corresponds substantially to the release rate index (RRI) of0.03. Based on the teachings described herein, a person of ordinaryskill in the art could determine the release rate profile withadditional data for an extended time of at least about one month, forexample at least about three months, six months or more, so as todetermine the release rate profile for an extended time.

FIG. 24B-1 shows rate of release as in FIG. 24A-1.

Example 14 Determination of Therapeutic Device Size and Lifetime Basedon Minimum Inhibitory Concentration in Vivo of Therapeutic Agent

Numerical calculations were performed to determine therapeutic devicesizes, release rate profiles and expected therapeutic agentconcentration in the reservoir. The concentration in the reservoir maycorrespond to the useful lifetime of the device, or time betweeninjections of therapeutic agent into the reservoir or other replacementof the therapeutic agent.

Table 6A shows the number days of therapeutic agent is released from thedevice with concentration amounts at or above the MIC. These number ofdays correspond to an effective lifetime of the device or effective timebetween injections into the device. The calculations show the number ofdays of the extended time release based the RRI and MIC for a 20 uLreservoir volume having a drug concentration disposed therein of 10mg/ml. The RRI ranged from 0.01 to 0.1 and the MIC ranged from 0.1 to10, and can be determined with experimental and clinical studies asdescribed herein. The half-life of therapeutic agent in the vitreous wasmodeled as 9 days, based on human data. The Cmax indicates the maximumconcentration of therapeutic agent in the vitreous humor, for examplewithin a few days of placement or injection of the therapeutic agent inthe device These data indicate that the device can maintain theconcentration of therapeutic agent for about 756 days, 385 days, 224days, and 62 day for MIC's of 0.1, 0.5, 1, 2 and 4 ug/ml, respectively.For example, the therapeutic agent may comprise Lucentis™ having an MICof about 0.5 and the device may maintain therapeutic concentrations ofthe agent for one year. These numerical data also show a concentrationof therapeutic agent released from the device within a range of thecurrent clinical bolus injections. For example, the Cmax ranges from 2.1to 11.9 based on the RRI from 0.01 to 0.1 respectively, such that themaximum release of therapeutic agent such as Lucentis™ is within a saferange for the patient.

A person of ordinary skill in the art can conduct experiments todetermine the stability of the therapeutic agent such as Lucentis™ inthe reservoir, and adjust the size of the reservoir, time betweeninjections or removal. The therapeutic agent can be selected andformulated so as to comprise a stability suitable for use in thetherapeutic device.

TABLE 6A Calculations for Time (days) above MIC (20 μL Reservoir Volume,T1/2 = 9 days, Drug Conc. in Reservoir = 10 mg/ml) Cmax MIC (μg/ml) RRI(μg/ml) 0.1 0.5 1 2 4 7 10 0.01 2.1 756 385 224 62 0 0 0 0.02 3.8 467280 200 119 0 0 0 0.04 6.5 281 188 148 108 66 0 0 0.06 8.6 209 147 12093 65 40 0 0.08 10.4 170 124 103 83 61 42 14 0.1 11.9 146 109 92 75 5842 30

Table 6B. Shows calculations for time (days) above the MIC for atherapeutic device comprising a 20 μL Volume, Vitreous T1/2=9 days, andDrug Conc. in Reservoir=40 mg/ml. The embodiments of Table 6B includesimilar components to the embodiments of Table 6A and the improved timeabove MIC achieved with concentration of 40 mg/ml. For example, the timeabove the MIC can be 1079, 706, 546, 385, 225, 95, for MIC's of 0.1 0.5,1, 2, 4, and 7 ug/ml, respectively. For example, the therapeutic agentmay comprise Lucentis™ having an MIC of about 0.5 and the device maymaintain therapeutic concentrations of the therapeutic agent for about 2years. These numerical data also show a concentration of therapeuticagent released from the device within a range of the current clinicalbolus injections. For example, the Cmax ranges from 8.4 to 47.6 based onthe RRI from 0.01 to 0.1 respectively, such that the maximum release oftherapeutic agent such as Lucentis™ is within a safe range for thepatient.

A person of ordinary skill in the art can conduct experiments todetermine the stability of the therapeutic agent such as Lucentis™ inthe reservoir, and adjust the size of the reservoir, time betweeninjections or removal. The therapeutic agent can be selected andformulated so as to comprise a stability suitable for use in thetherapeutic device.

TABLE 6B Calculations for Time (days) above MIC (20 μL Volume, T1/2 = 9days, Drug Conc. in Reservoir = 40 mg/ml) Cmax MIC (μg/ml) RRI (μg/ml)0.1 0.5 1 2 4 7 10 0.01 8.4 1079 706 546 385 225 95 0 0.02 15.1 626 440360 280 200 135 93 0.04 25.9 361 268 228 188 148 115 94 0.06 34.4 262200 174 147 120 98 84 0.08 41.5 210 164 144 124 103 87 76 0.1 47.6 179141 125 109 92 79 70

Table 6C. Shows calculations for time (days) above the MIC for atherapeutic device comprising a 50 μL Volume, Vitreous T1/2=9 days, andDrug Conc. in Reservoir=40 mg/ml. The embodiments of Table 6B includesimilar components to the embodiments of Table 6A and the improved timeabove MIC achieved with concentration of 40 mg/ml. For example, the timeabove the MIC can be 2706, 1737, 1347, 944, 542 and 218, for MIC's of0.1 0.5, 1, 2, 4, and 7 ug/ml, respectively. For example, thetherapeutic agent may comprise Lucentis™ having an MIC of about 0.5 andthe device may maintain therapeutic concentrations of the therapeuticagent for more than about 2 years. These numerical data also show aconcentration of therapeutic agent released from the device within arange of the current clinical bolus injections. For example, the Cmaxranges from 9.1 to 64.7 ug/ml based on the RRI from 0.01 to 0.1respectively, such that the maximum release of therapeutic agent such asLucentis™ is within a safe range for the patient.

A person of ordinary skill in the art can conduct experiments todetermine the stability of the therapeutic agent such as Lucentis™ inthe reservoir, and adjust the size of the reservoir, time betweeninjections or removal. The therapeutic agent can be selected andformulated so as to comprise a stability suitable for use in thetherapeutic device.

TABLE 6C Calculations for Time (days) above MIC (50 μL Volume, T1/2 = 9days, Drug Conc. in Reservoir = 40 mg/ml) Cmax MIC (μg/ml) RRI (μg/ml)0.1 0.5 1 2 4 7 10 0.01 9.1 2706 1737 1347 944 542 218 0 0.02 17.2 15601082 880 679 478 316 213 0.04 31.5 887 648 547 446 346 265 213 0.06 43.8635 476 408 341 274 220 186 0.08 54.8 501 381 331 281 230 190 164 0.164.7 417 321 281 240 200 168 147

The examples shown in Tables 6A to 6C can be modified by one of ordinaryskill in the art in many ways based on the teachings described herein.For example, the 50 uL reservoir may comprise an expanded configurationof the reservoir after injection of the therapeutic device. Thereservoir and/or quantity of therapeutic agent can be adjusted so as toprovide release for a desired extended time.

The porous frit structure as described herein can be used with manytherapeutic agents, and may limit release of therapeutic agent that hasdegraded so as to form a particulate, for example. Work in relation toembodiments suggests that at least some therapeutic agents can degradeso as to form a particulate and that the particulate comprising degradedtherapeutic agent may have an undesired effect on the patient, and theporous frit structure as described herein may at least partially filtersuch particulate so as to inhibit potential side effects of degradedtherapeutic agent.

Table 6D shows examples of sizes of therapeutic devices that can beconstructed in accordance with the teachings described herein, so as toprovide a suitable volume of the drug reservoir within the container andsuch devices may comprise many lengths, widths and structures asdescribed herein. For example the frit outside diameter (hereinafter“OD”) can be configured in many ways and may comprise about 1 mm, forexample, or about 0.5 mm. The length of the frit (thickness) maycomprise about 1 mm. The volume of the frit can be, for example, about0.785 uL, or about 0.196 uL, for example. The volume of the reservoircan be from about 0.4 uL to about 160 uL, for example. The volume of thetherapeutic device can be from about 0.6 uL to about 157 uL, and can bepositioned in many ways, for example with a lumen and may comprise asubstantially fixed volume reservoir or an expandable reservoir. Thecross sectional width of the device may correspond to many sizes, forexample many radii, and the radius can be within a range from about 0.3mm to about 3.5 mm, for example. The cross-section width andcorresponding diameters of the device can be within a range from about0.6 mm to about 7 mm. The length of the device, including the porousstructure, container and retention structure can be many sizes and canbe within a range from about 2 mm to about 4 mm, for example. The devicemay comprise a substantially fixed diameter, or alternatively can beexpandable, and may comprise fixed or expandable retention structures,as described herein.

TABLE 6D Frit OD (mm) 1 0.5 Frit Length (mm) 1 1 Frit Vol. (uL) 0.7850.19625 Vol Res (uL) 0.4 2 4 8 16 27 31 39 63 110 157 Vol Frit (uL)0.19625 0.19625 0.785 0.785  0.785  0.785  0.785  0.785  0.785  0.785 0.785 Vol Device (uL) 0.59625 2.19625 4.785 8.785 16.785 27.785 31.78539.785 63.785 110.785 157.785 Radius squared 0.09 0.3 0.4 0.7  1.3  2.2 2.5  3.2  5.1  8.8  12.6 Radius (mm) 0.3 0.5 0.6 0.8  1.2  1.5  1.6 1.8  2.3  3.0  3.5 OD (mm) 0.6(4) 1.1(3) 1.2(3) 1.7(3)  2.3(3)  3.0(2) 3.2(2)  3.6(2)  4.5(2)  5.9(2)  7.1(2) Dev Length (mm) 2.0(6) 2.5(5)4.0(1) 4.0(1)  4.0(1)  4.0(1)  4.0(1)  4.0(1)  4.0(1)  4.0(1)  4.0(1)(1)Fixed penetration upper limit (2)May use non simple cylinder designto decrease incision length, for example expandable reservoir (3)ODaccommodates 1 mm diameter porous frit structure and satisfies incisionlength limit (4)Device OD may use a smaller porous frit structure(5)Length reduced to drive OD to accommodate porous frit structure(6)Length reduced to drive OD to accommodate porous frit structure, andDevice OD may use smaller frit

Example 15A Calculation and Measurement of Small Release Rate Profilesas a Model for a Therapeutic Agent Released Through the Porous FritStructure

Studies of the release of fluorescein from reservoirs through porousfrit structures were conducted so as to determine the release of smallmolecule drugs through the porous frit structure. The fluorescein modelshows that the porous frit structures and reservoirs as described hereinare suitable for use with small molecule drug deliver. The releaseprofiles of Avastin™, Lucentis™ and BSA in conjunction with thefluorescein data show that the porous frit structures and reservoirs canbe used for sustained release of many drugs, molecules and therapeuticagents of many molecular weights and sizes.

FIG. 25A shows cumulative release for fluorescein through a 0.2 mediagrade porous frit structure. The experiment used: 2 mg/mL Fluoresceinsodium; Frit #2 (0.031×0.049″, media grade 0.2 um, 316L SS, MottCorporation); Machined polycarbonate surrogate with screw; 37 C. Thefluorescein samples were assayed by UV absorbance at 492 nm with a platereader. The determined RRI based on measurements is 0.02, consistentwith the model for release of the therapeutic agents as describedherein.

FIG. 25A-1 shows cumulative release to about 90 days for fluoresceinthrough a 0.2 media grade porous frit structure as in FIG. 25A. The meanRRI based upon the first four data points was 0.02 mm. The mean RRI torelease for 90 days (excluding the first point) is 0.026 mm. These datashow stability of the rate of release and that the porous frit structurecan be used for small molecule delivery or large molecule delivery, orcombinations thereof.

FIG. 25B shows rate of release as in FIG. 25A. The release rate datashow a rate of release from about 1.0 ug per day to about 1.8 ug perday. Although the initial release rate at the first day is slightlylower than subsequent rates, the rate of release is sufficiently high toprovide therapeutic effect in accordance with the drug release model.Although there can be an initial period of about a day for the releaserate profile to develop, possibly related to wetting of theinterconnecting channels of the porous structure, the release rateprofile corresponds substantially to the release rate index (RRI) of0.02. Based on the teachings described herein, a person of ordinaryskill in the art could determine the release rate profile withadditional data for an extended time of at least about one month, forexample at least about three months, six months or more, so as todetermine the release rate profile for an extended time.

FIG. 25B-1 shows rate of release as in FIG. 25A-1.

Example 15B Measured Release Rate Profiles for Lucentis™ Through thePorous Frit Structures

The experiments used: 10 mg/mL Lucentis™; Machined poly(methylmethacrylate) surrogate with screw; and a Reservoir Volume 30 uL; 37 C.All porous frit structures are 316L SS, Mott Corporation. Data shown aremeasured data from all devices except for a few samples that showedeither bubble growth or low receiver volume.

Table 6E shows results for 39 out of 48 devices were included in thetable and graphs shown below. The data from the in vitro studies shownin Table 6E show that Lucentis™ can be delivered with the device havingporous frit structure. The diameter ranged from 0.031″ to 0.038″, andthe length ranged from 0.029 to 0.049. The media grade ranged from 0.1to 0.3, and the RRI ranged from 0.014 to 0.090. The data show very lowvariability suitable in in vivo human treatment, with the % CV below 10%in all insances, and less than 3% for four of five device configurationsmeasured.

Although some of the measurements were excluded, this exlusion isappropriate and associated with in vitro testing conditions that differsubstantially from the in vivo model. Five devices were excluded due tobubble growth (10%), and four were excluded due to receiver volumeissues at one timepoint for that device (8%). The latter can be anexperimental error associated with the volume of the receiver below theassumed value due to evaporation from inadequately sealed vials or dueto pipetting error. In some instances the in vitro experimental testapparatus can be sensitive to bubble formation that may differsubstantially from the in vivo model as the living eye can resorb oxygenfrom the therapeutic devices. Bubbles can form as receiver fluid isheated to 37° C. and gas concentrations are greater than theirsolubilities at 37° C. To minimize the occurance of bubble formation,receiver solutions were degassed before insertion of the devices. Theseexperimental in vitro studies suggest that degassing of samples can behelpful with the in vitro assays.

TABLE 6E Media Frit Dimensions Grade RRI Number of Dia Length (μm) (mm)% CV Replicates 0.038″ 0.029″ 0.3 0.090 2.1% 6 0.038″ 0.029″ 0.2 0.0612.8% 14 0.038″ 0.029″ 0.1 0.039 2.3% 5 0.031″ 0.049″ 0.2 0.021 9.9% 120.031″ 0.049″ 0.1 0.014 2.5% 2

FIG. 25C shows cumulative release to about thirty days for Lucentis™through a 0.2 media grade porous frit structure having a diameter of0.038 in and a length (thickness) of 0.029, corresponding to a releaserate of 0.061 as shown in the second row of Table 6E.

FIG. 25D shows rates of release of the devices as in FIG. 25C.

FIG. 25E shows cumulative relase to about thirty days for Lucentis™ for30 uL devices having a RRI's from about 0.090 to about 0.015.

FIG. 25F shows rates of release of the devices as in FIG. 25E.

These above experimentally measured data show stable release of theLucentis™ for 30 days for a wide range of frit diameters, thickesses andmedia grades consistent with the release rate model of the porousstructure and reservoir as described herein. For example, the mediagrade, thickness, diameter and reservoir volume can be tuned to providesustained release for a predetermined period of time above apredetermined targeted minimum inhibitory concentration. When combinedwith the Avastin™ and Fluorescein data, these data show that stablerelease can be achieved for extended times for many therapeutic agentsconsistent with the release model as described herein.

Example 16 Scanning Electron Micrographs of Porous Frit Structures

FIGS. 26A and 26B show scanning electron microscope images fromfractured edges of porous frit structures of 0.2 media grade and 0.5media grade porous material, respectively. The commercially availablesamples were obtained from Mott Corporation and comprised 316L stainlesssteel. The samples were mechanically fractured so as to show the porousstructure and interconnecting channels within the material to releasethe therapeutic agent. The micrograph images show a plurality ofinterconnecting channels disposed between openings of the first surfaceand openings of the second surface.

FIGS. 27A and 27B show scanning electron microscope images from surfacesof porous frit structures of media grade of 0.2 and 0.5, respectively,from the samples of FIGS. 26A and 26B. The images show a plurality ofopenings on the surface connected with interconnecting channels as inFIGS. 26A and 26B.

Example 17 Porous Frit Structure Mechanical Flow Testing to IdentifyPorous Frit Structures Suitable for Use with Therapeutic Agent DeliveryDevices

The relative characteristics of sample elements can be determined bysubjecting the frit to a number of mechanical tests, including but notlimited to pressure decay and flow. These tests can be combined withdrug release rate information, for example the RRI, so as to determinethe release profile of the devices. These tests can be used with theporous structure positioned on the therapeutic device, so as to quantifyflow through the porous structure of the device and determine suitableof the porous structure. Similar tests can be used to quantify theporous structure prior to mounting on the therapeutic device. At leastsome of the therapeutic devices can be evaluated with the gas flow ofthe porous structure mounted on a partially assembled therapeuticdevice, for example as a quality control check In some embodiments, theflow test can be performed on the partially assembled or substantiallyassembled therapeutic device prior to insertion of the therapeutic agentinto the reservoir and prior to insertion into the patient, so as toensure that the porous structure is suitable for release of thetherapeutic agent and affixed to the device, for example a support ofthe therapeutic device.

These tests may utilize a variety of working fluids, but will mostlikely use a readily available gas such as air or nitrogen. To date,flow and pressure decay tests have been used to identify different fritcharacteristics that may be correlated to other test results such aschemical or pharmacologic performance.

Fixturing

Each of the test methods above may use a mechanical connection of thetest specimen to the test hardware and a number of techniques have beenexplored and employed. These fixtures include a both a means of reliablysecuring the specimen (such as heat recoverable tubing, elastic tubing,press fits into relatively rigid components, etc.) and a means ofcoupling (such as a luer, barbed fitting, quick connect coupling, etc.)that allow convenient and repeatable attachment to the test hardware.

Test Hardware

Each of the desired tests can be developed using commercially availablesolutions, or by assembling readily available instrumentation to createa custom test arrangement. Again, both of these approaches have beenevaluated. A working system will consist of a means for connecting atest specimen, a controllable source (usually, but not limited topressure), a manometer (or other pressure measurement device), and oneor more transducers (pressure, flow, etc.) used to measure the testconditions and/or gather data for further analysis.

Example 17A Pressure Decay Test to Identify Porous Structures Suitablefor Use with Therapeutic Drug Delivery Devices

FIG. 28 shows a pressure decay test and test apparatus for use with aporous structure so as to identify porous frit structures suitable foruse with therapeutic devices in accordance with embodiments describedherein.

One method of pressure decay testing is performed with the hardwareshown schematically in FIG. 28. An initial pressure is applied to thesystem by an outside source such as a syringe, compressed air,compressed nitrogen, etc. The manometer may be configured to displaysimply the source gage pressure, or the actual differential pressureacross the specimen. One side of the fixtured specimen is normally opento atmosphere, creating a pressure which will decay at a rate determinedby the properties of the frit being tested. The instantaneous pressuremay be measured by a pressure transducer that converts and supplies asignal to a data acquisition module (DAQ) that transfers data to acomputer. The rate of pressure drop is then recorded and can be used forcomparison to the performance of other fits or an acceptabilityrequirement/specification. This comparison may be made by grosslycomparing the pressure at a given time, or by directly comparing theoutput pressure decay curves.

An example test procedure would pressurize the system to slightlygreater than 400 mmHg as displayed by the manometer. The computer andDAQ are configured to begin data acquisition as the pressure drops below400 mmHg, and a data point is taken approximately every 0.109 seconds.While the test can be stopped at any time, it is likely that standarddiscreet points along the course of pressure decay data would beselected so as to allow direct comparison of frit flow performance (e.g.time for decay from 400 mmHg to 300 mmHg, and from 400 mmHg to 200mmHg.)

Example 17B Pressure Decay Test to Identify Porous Structures Suitablefor Use with Therapeutic Drug Delivery Devices

FIG. 29 shows a pressure flow test and test apparatus suitable for usewith a porous structure so as to identify porous frit structuressuitable for use with therapeutic devices in accordance with embodimentsdescribed herein.

Using a similar hardware set-up, flow thru the test specimen can also becharacterized. In this test, the source pressure is constantly regulatedto a known pressure and the flow of a working fluid is allowed to flowthru a mass flow meter and then thru the fixtured test frit. As in thepressure decay test, the specific characteristics of the frit determinethat rate at which the working fluid will flow through the system. Foradditional accuracy, pressure at the otherwise open end of the fixturetest frit may be regulated to control the backpressure, and thereforethe pressure drop across the specimen.

Flow testing may have advantages over pressure decay testing due to theinstantaneous nature of the method. Rather than waiting for the pressureto drop, the flow thru a sample should stabilize quickly enablingtesting of large number of samples to be performed in rapid fashion.

In an example test procedure, a regulated compressed cylinder wouldsupply the system with a constant source pressure of 30 psig and aconstant back pressure of 1 psig. The test fluid would flow through thetest frit at a characteristic rate (which is dependent on the pressure,but is expected to be in the 10-500 sccm range) as measured by the massflow meter.

Example 17C Determination of Therapeutic Release Rate Based on Gas Flow

Table 7 shows a table that can be used to determine release oftherapeutic agent, for example the RRI, based on the flow of a gas suchas oxygen or nitrogen through the porous structure. The flow through theporous structure can be measured with a decay time of the gas pressure,for with the flow rate across the porous structure with a pressure dropacross the porous frit structure, as described herein. The flow rate andRRI can be determined based on the media grade of the material, forexample as commercially available media grade material available fromMott Corp. The therapeutic agent can be measured through the porousstructure, or a similar test molecule. The initial measurements measuredthe RRI for Avastin™ with the porous frit structures shown. Based on theteachings described herein, a person of ordinary skill in the art canconduct experiments to determine empirically the correspondence of flowrate with a gas to the release rate of the therapeutic agent.

TABLE 7 Media O.D. Length RRI 300 200 Grade (in.) (in.) Flow Decay Decay0.2 0.031 0.049 0.019 106 256 0.2 0.038 0.029 0.034 0.1 0.038 0.0290.014 81 201 0.2 0.038 0.029 0.033 31 78

The above partially populated table shows the amount and nature of fritdata that can collected. It is contemplated to use some form ofnon-destructive testing (i.e. not drug release testing) so as to enable:

-   a) QC receiving inspection testing of frits-   b) QC final device assembly testing

One of ordinary skill can demonstrate a correlation between one or more“flow” tests and the actual drug release testing which relies ondiffusion rather than forced gas flow. The data suggests that flowtesting of frits can be both repeatable and falls in line withexpectations.

Preliminary testing also indicates that the test for the frit alone canbe substantially similar to the frit as an assembled device.

Example 18 Determination of Minimum in Vivo Inhibitory Concentration ofLucentis™ in Humans

Although administration of the standard dose of Lucentis™ (500 μg) viadirect intravitreal injection has been shown to be effective in reducingsymptoms of patients suffering from wet AMD, the below clinical studiesindicate that a lower concentration can be used to treat wet AMD. Adevice as described herein can be used to treat AMD with a minimuminhibitory concentration in vivo in human patients (hereinafter “MIC”)with a smaller amount than corresponds to the 500 μg monthly bolusinjection. For example, 5 ug Lucentis™ injections can be administered soas to obtain a concentration profiles in situ in humans in accordancewith Table 4D and FIG. 19A above.

The study was designed to detect quickly a positive response toLucentis™ treatment. A reduction of retinal thickness is an indicator ofpositive response to Lucentis™ therapy and a marker of drug effect thatcan be used to quickly identify a positive effect of drug treatment. Thereduction in retinal thickness corresponds to subsequent improvement invision. Hence, the low dose MIC study assessed the condition of retinalthickness both before and after patient's exposure to low dose bolusadministration of Lucentis™, so as to determine the MIC.

OCT (Optical Coherence Tomography) imaging was used to asses thecondition of the region of the macula at the back surface of the treatedeye. The OCT technique relies on the measurement of certain propertiesof light (e.g. echo time, intensity of reflection) that has beendirected at the area of study and can measure very small amounts ofreflected light. Because these cellular features are essentiallytransparent it is possible to use OCT methodology to generate threedimensional representations of the area.

The anatomical region of patients suffering from wet AMD typicallyinvolves disturbances to the structural make-up of the various cellularlayers of the back surface of the eye, notably including areas ofretinal thickening often involving accumulations of subretinal fluid. Inmore advanced stages these areas of fluid accumulation often involvecyst-like formations easily evaluated via OCT.

The OCT images generated in the study enabled of various types ofassessments to be made regarding the condition of the anatomical regionof interest. One type of OCT image comprises a topographic map of theentire region of the macula. This image type is referred to as the“macular cube”. The macular cube OCT images are typically displayed ascolor images and in the case of the macular cube the image provides anindication of overall topography of the disease/lesion location. Thesemacular cube images were used identify regions of the macular ofinterest.

The regions of interest were analyzed with a two dimensionalrepresentation of the cross section of the retinal wall at onelongitudinal scan location of the OCT image. In these “OCT scan” imagesis it possible to interrogate very local areas of interest morespecifically. The OCT scans were carefully selected to directly comparethe thickness and anatomical structure of specific sites within alesion, pre and post treatment, for the purpose of assessing the effectof injected drug including a reduction in sub-retinal fluid.

Macular cube images and OCT scan images were measured before and afterLucentis™ treatment for each patient enrolled in the study. The OCTimages were measured the day after injection and at 2-3 days postinjection. An ophthalmologist reviewed the OCT images from the patientsenrolled in the study, and patients were considered to have a respondedto Lucentis™ treatment when the OCT scans showed a decrease in size ofthe lesion from one or more of the post-injection examinations.

FIG. 30A-1 shows an example of an OCT macular cube OCT image used toidentify a region of interest (black arrow) and determine the responseto treatment.

FIGS. 30B-1, 30B-2 and 30B-3 shows an example of a series of OCT scanimages measured at pre-injection, one day post-injection and one weekpost-injection, respectively of sections of the region of interest.

Table 8 shows the results for 9 patients enrolled in the study. Thepatients received doses from 5 to 20 ug, corresponding to initialLucentis™ concentrations in the vitreous from 1 to 4 ug/ml. Based on theabove criteria, a positive response was identified in all 9 patients. Inat least some instances with the 5 um injection, the decrease in size ofthe lesion was noted approximately 2-4 days post-op, and the decreasewas substantially attenuated by one week post-op, consistent with theapproximately 9 day in vivo half-life of Lucentis™. These data indicatedthat the MIC for a sustained release device may be approximately 1 ugper ml or less. As the therapeutic agent may have a cumulative effect,the MIC can be lower for a sustained release as described herein thanthe bolus injection described with reference to the MIC study. Furtherstudies can be conducted by one or ordinary skill in the based on theteachings described herein to determine empirically the MIC for asustained release device and cumulative effect of the drug over the timeof release.

TABLE XX Patient # 1 2 3 4 5 6 7 8 9 Lowest Dose 10 20 20 5 20 5 5 5 5Administered (μg) Estimated Initial 2 4 4 1 4 1 1 1 1 Drug Conc. inVitreous (μg/mL) Treatment Yes Yes Yes Yes Yes Yes Yes Yes Yes EffectObserved?

FIGS. 31A and 31B show experimental implantation of therapeutic devicesinto the pars plana region 25 of a rabbit eye. Approximately 4prototypes of the device as shown in FIG. 7A to 7B-6F were implantedinto the rabbit eye. The retention structure of each devices comprised asubstantially clear and transparent oval flange 122 positioned on thesclera under the conjunctiva. The clear and transparent flange 122permits visualization of the interface of the scleral incision andnarrow portion 120N of the retention structure, such that sealing of theretention structure to the sclera can be evaluation. The retentionstructure of each device also comprise an access port 180 having asubstantially clear penetrable barrier 184 so as to permit dark fieldvisualization of the location of the implanted device. The narrowportion 120N of the retention structure is disposed under thetransparent flange, and barrier 160 has the oval shape so to define thenarrow portion of the retention structure.

These studies showed that the retention structure comprising the ovalflange and oval narrow portion can seal the incision formed in thesclera and permit dark field visualization of the implanted device. Thedevice can be implanted temporally in the patient, for examplesuperior/temporally or inferior/temporally such that the implant can bedisposed temporally and under the eyelid so as to have a minimal effecton vision and appearance of the patient.

While the exemplary embodiments have been described in some detail, byway of example and for clarity of understanding, those of skill in theart will recognize that a variety of modifications, adaptations, andchanges may be employed. Hence, the scope of the present inventionshould be limited solely by the appended claims.

TABLE 1A Therapeutic Agent List Molecular Generic Name Brands(Companies) Category Indication Weight 2-Methoxyestradiol (PalomaPharmaceuticals) Angiogenesis inhibitors AMD analogs 3-aminothalidomide13-cis retinoic acid Accutane TM (Roche Pharmaceuticals) A0003 (AqumenBioPharmaceuticals) A0003 AMD A5b1 integrin (Jerini Ophthalmic);(Ophthotech) Inhibitors of a5b1 integrin AMD inhibitor AbarelixPlenaxis ™ (Praecis Pharmaceuticals) Anti-Testosterone Agents; Forpalliative treatment of advanced 37731 Antineoplastic Agents prostatecancer. Abatacept Orencia ™ (Bristol-Myers Squibb) Antirheumatic AgentsFor the second line reduction of the signs 37697 and symptoms ofmoderate-to-severe active rheumatoid arthritis, inducing inducing majorclinical response, slowing the progression of structural damage, andimproving physical function in adult patients who have AbciximabReoPro ™; ReoPro ™ (Centocor) Anticoagulants; For treatment ofmyocardial infarction, 42632 Antiplatelet Agents adjunct to percutaneousoronary intervention, unstable angina ABT-578 (Abbott Laboratories)Limus Immunophilin Binding Compounds Acetonide Adalimumab Humira ™(Abbott Laboratories) Antirheumatic Agents; For treatment of rheumatoidarthritis 25645 Immunomodulatory Agents Aldesleukin Proleukin ™;Proleukin ™ (Chiron Antineoplastic Agents For treatment of adults withmetastatic 61118 Corp) renal cell carcinoma Alefacept Amevive ™Immunomodulatory For treatment of moderate to severe 42632 Agents;chronic plaque psoriasis Immunosuppressive Agents Alemtuzumab Campath ™;Campath ™ (ILEX Antineoplastic Agents For treatment of B-cell chronic6614 Pharmaceuticals LP); MabCampath ™ lymphocytic leukemiaAlpha-1-proteinase Aralast ™ (Baxter); Prolastin ™ Enzyme ReplacementFor treatment of panacinar emphysema 28518 inhibitor (TalecrisBiotherapeutics C formerly Agents Bayer) Alteplase Activase ™ (GenentechInc) Thrombolytic Agents For management of acute myocardial 54732infarction, acute ischemic strok and for lysis of acute pulmonary emboliAMG-1470 Anakinra Kineret ™ (Amgen Inc) Anti-Inflammatory Agents, Forthe treatment of adult rheumatoid 65403 Non-Steroidal; arthritis.Antirheumatic Agents; Immunomodulatory Agents Anecortave acetateAngiostatin Anistreplase Eminase ™ (Wulfing Pharma GmbH) ThrombolyticAgents For lysis of acute pulmonary emboli, 54732 intracoronary emboliand management of myocardial infarction Anti-angiogenesis (Eyecopharm)Anti-angiogenesis AMD peptides peptides Anti-angiogenesis (TRACONPharma) Anti-angiogenesis AMD antibodies, antibodies TRC093, TRC105Anti-angiogeric Icon-1 ™ (Iconic Therapeutics) Anti-angiogeric AMDbifunctional protein bifunctional protein, Icon-1 Anti-endothelialgrowth factor Antihemophilic Advate ™; Alphanate ™; Bioclate ™;Coagulants; Thrombotic For the treatment of hemophilia A, von 70037Factor Helixate ™; Helixate FS ™; Hemofil Agents Willebrand diseae andFactor XIII M ™; Humate-P ™; Hyate:C ™; Koate- deficiency HP ™;Kogenate ™; Kogenate FS ™; Monarc-M ™; Monoclate-P ™; ReFacto ™;Xyntha ™ Antithymocyte Genzyme); Thymoglobulin ™ Immunomodulatory AgentsFor prevention of renal transplant 37173 globulin (SangStat Medicalrejection Anti-hypertensive (MacuCLEAR) Anti-hypertensive MC1101 AMDMC1101 Anti-platelet devired growth factor Anti-VEGF (Neurotech);Avastin ™ (NeoVista) Anti-VEGF AMD AP23841 (Ariad) Limus ImmunophilinBinding Compounds Aprotinin Trasylol ™ Antifibrinolytic Agents Forprophylactic use to reduce 90569 perioperative blood loss and the needfor blood transfusion in patients undergoing cardiopulmonary bypass inthe course of coronary artery bypass graft surgery who are at anincreased risk for blood loss and blood transfusio ArcitumomabCEA-Scan ™ Diagnostic Agents; For imaging colorectal tumors 57561Imaging Agents Asparaginase Elspar ™ (Merck & Co. Inc) AntineoplasticAgents For treatment of acute lympocytic 132.118 leukemia andnon-Hodgkins lymphoma Axitinib Tyrosine Kinase Inhibitors 386Basiliximab Simulect ™ (Novartis Immunomodulatory For prophylactictreatment of kidney 61118 Pharmaceuticals) Agents; transplant rejectionImmunosuppressive Agents Becaplermin Regranex ™; Regranex ™ (OMJAnti-Ulcer Agents; Topical For topical treatment of skin ulcers (from123969 Pharmaceuticals) diabetes) Bevacizumab Avastin ™; Avastin ™(Genentech Inc) Antiangiogenesis Agents; For treatment of metastaticcolorectal 27043 Antineoplastic Agents cancer Bivalirudin Angiomax ™;Angiomax ™ (Medicines Anticoagulants; For treatment of heparin-induced70037 Co or MDCO); Angiox ™ Antithrombotic Agents thrombocytopeniaBortezomib Proteosome Inhibitors Bosutinib Tyrosine Kinase Inhibitors530 Botulinum Toxin BOTOX ™ (Allegran Inc); BOTOX Anti-Wrinkle Agents;For the treatment of cervical dystonia in 23315 Type A Cosmetic ™(Allegran Inc); Botox ™; Antidystonic Agents; adults to decrease theseverity of Dysport ™ Neuromuscular Blocking abnormal head position andneck pain Agents associated with cervical dystonia. Also for thetreatment of severe primary axillary hyperhidrosis that is inadequatelymanaged with topical Botulinum Toxin Myobloc ™ (Solstice Neurosciences);Antidystonic Agents For the treatment of patients with cervical 12902Type B Neurobloc ™ (Solstice Neurosciences) dystonia to reduce theseverity of abnormal head position and neck pain associated withcervical dystonia. C5 inhibitor (Jerini Ophthalmic); (Ophthotech)Inhibitors of C5 AMD Canstatin Capromab ProstaScint ™ (Cytogen Corp)Imaging Agents For diagnosis of prostate cancer and 84331 detection ofintra-pelvic metastases Captopril ACE Inhibitors CCI-779 (Wyeth) LimusImmunophilin Binding Compounds Cediranib Tyrosine Kinase Inhibitors 450Celecoxib Cyclooxygenase Inhibitors Cetrorelix Cetrotide ™ HormoneAntagonists; For the inhibition of premature LH surges 78617 InfertilityAgents in women undergoing controlled ovarian stimulation CetuximabErbitux ™; Erbitux ™ (ImClone Antineoplastic Agents For treatment ofmetastatic colorectal 42632 Systems Inc) cancer. ChoriogonadotropinNovarel ™; Ovidrel ™; Pregnyl ™; Fertility Agents; For the treatment offemale infertility 78617 alfa Profasi ™ Gonadotropins Cilaryneurotrophic (Neurotech) Cilary neurotrophic factor AMD factorCoagulation Factor Benefix ™ (Genetics Institute) Coagulants; ThromboticFor treatment of hemophilia (Christmas 267012 IX Agents disease).Coagulation factor NovoSeven ™ (Novo Nordisk) Coagulants; Thrombotic Fortreatment of hemorrhagic 54732 VIIa Agents complications in hemophilia Aand B Colchicines Collagenase Cordase ™; Santyl ™ (Advance Anti-UlcerAgents; Topical For treatment of chronic dermal ulcers 138885Biofactures Corp); Xiaflextm ™ and severe skin burns Complement factor(Optherion); (Taligen Therapeutics) Complement factor H AMD Hrecombinant recombinant Compstatin (Potentia Pharmaceuticals) ComplementFactor C3 AMD derivative peptide, Inhibitors; Compstatin POT-4Derivative Peptides Corticotropin ACTH ™; Acethropan ™; Acortan ™;Diagnostic Agents For use as a diagnostic agent in the 33927 Acthar ™;Exacthin ™; H.P. Acthar screening of patients presumed to have Gel ™;Isactid ™; Purified cortrophin adrenocortical insufficiency. gel ™;Reacthin ™; Solacthyl ™; Tubex Cosyntropin Cortrosyn ™; Synacthendepot ™ Diagnostic Agents For use as a diagnostic agent in the 33927screening of patients presumed to have adrenocortical insufficiency.Cyclophilins Limus Immunophilin Binding Compounds Cyclosporine Gengraf ™(Abbott labs); Neoral ™ Antifungal Agents; For treatment of transplantrejection, 32953 (Novartis); Restasis ™; Restasis ™ AntirheumaticAgents; rheumatoid arthritis, severe psoriasis (Allergan Inc);Sandimmune ™ Dermatologic Agents; (Novartis); Sangcya ™ EnzymeInhibitors; Immunomodulatory Agents; Immunosuppressive Agents DaclizumabZenapax ™ (Hoffmann-La Roche Inc) Immunomodulatory For prevention ofrenal transplant 61118 Agents; rejection Immunosuppressive AgentsDarbepoetin alfa Aranesp ™ (Amgen Inc.) Antianemic Agents For thetreatment of anemia (from renal 55066 transplants or certain HIVtreatment) Dasatinib Tyrosine Kinase Inhibitors 488 DefibrotideDasovas ™; Noravid ™; Prociclide ™ Antithrombotic Agents Defibrotide isused to treat or prevent a 36512 failure of normal blood flow (occlusivevenous disease, OVD) in the liver of patients who have had bone marrowtransplants or received certain drugs such as oral estrogens,mercaptopurine, and many others. Denileukin diftitox Ontak ™Antineoplastic Agents For treatment of cutaneous T-cell 61118 lymphomaDesmopressin Adiuretin ™; Concentraid ™; Stimate ™ Antidiuretic Agents;For the management of primary nocturnal 46800 Hemostatics; Renalenuresis and indicated as antidiuretic Agents replacement therapy in themanagement of central diabetes insipidus and for the management of thetemporary polyuria and polydipsia following head trauma or surgery inthe pitu Dexamethasone Ozurdex ™ (Allergan) Glucocorticoid DME,inflammation, macular edema 392 following branch retinal vein occlusion(BRVO) or central retinal vein occlusion (CRVO) DiclofenacCyclooxygenase Inhibitors Dithiocarbamate NFκB Inhibitor Dornase AlfaDilor ™; Dilor-400 ™; Lufyllin ™; Enzyme Replacement For the treatmentof cystic fibrosis. 7656 Lufyllin-400 ™; Neothylline ™; Agents (doublePulmozyme ™ (Genentech Inc) strand) Drotrecogin alfa Xigris ™; Xigris ™(Eli Lilly & Co) Antisepsis Agents For treatment of severe sepsis 267012Eculizumab Soliris ™; Soliris ™ (Alexion For the treatment of patientswith 188333 Pharmaceuticals) paroxysmal nocturnal hemoglobinuria (PNH)to reduce hemolysis. Efalizumab Raptiva ™; Raptiva ™ (Genentech Inc)Immunomodulatory For the treatment of adult patients with 128771 Agents;moderate to severe chronic plaque Immunosuppressive psoriasis, who arecandidates for Agents phototherapy or systemic therapy. EndostatinEnfuvirtide Fuzeon ™; Fuzeon ™ (Roche Anti-HIV Agents; HIV For treatmentof HIV AIDS 16768 Pharmaceuticals) Fusion Inhibitors Epoetin alfaEpogen ™ (Amgen Inc.); Epogin ™ Antianemic Agents For treatment ofanemia (from renal 55066 (Chugai); Epomax ™ (Elanex); transplants orcertain HIV treatment) Eprex ™ (Janssen-Cilag. Ortho Biologics LLC);NeoRecormon ™ (Roche); Procrit ™ (Ortho Biotech); Recormon ™ (Roche)Eptifibatide Integrilin ™; Integrilin ™ (Millennium Anticoagulants; Fortreatment of myocardial infarction and 7128 Pharm) Antiplatelet Agents;acute coronary syndrome. Platelet Aggregation Inhibitors ErlotinibTyrosine Kinase Inhibitors 393 Etanercept Enbrel ™; Enbrel ™ (ImmunexCorp) Antirheumatic Agents; For treatment of severe adult and ocalizi25645 Immunomodulatory Agents rheumatoid arthritis Everolimus LimusImmunophilin Binding Compounds Exenatide Byetta ™; Byetta ™ (Amylin/EliLilly) Indicated as adjunctive therapy to 53060 improve glycemic controlin patients with Type 2 diabetes mellitus who are taking metformin, asulfonylurea, or a combination of both, but have not achieved adequateglycemic control. Felypressin Felipresina ™ [INN-Spanish]; Renal Agents;For use as an alternative to adrenaline as 46800 Felipressina ™ [DCIT];Felypressin ™ Vasoconstrictor Agents a ocalizing agent, provided thatlocal [USAN:BAN:INN]; Felypressine ™ ischaemia is not essential.[INN-French]; Felypressinum ™ [INN- Latin]; Octapressin ™ Fenretinide(Sirion Therapeutics) Binding Protein Antagonist AMD for Oral Vitamin AFilgrastim Neupogen ™ (Amgen Inc.) Anti-Infective Agents; Increasesleukocyte production, for 28518 Antineutropenic Agents; treatment innon-myeloid Immunomodulatory Agents cancer, neutropenia and bone marrowtransplant FK605-binding Limus Immunophilin proteins, FKBPs BindingCompounds Fluocinolone Retisert ™ (Bausch & Lomb); Iluvien ™Glucocorticoid Retinal inflammation, diabetic macular 453 Acetonide(Alimera Sciences, Inc.) edema Follitropin beta Follistim ™ (Organon);Gonal F ™; Fertility Agents For treatment of female infertility 78296Gonal-F ™ Fumagillin Galsulfase Naglazyme ™; Naglazyme ™ EnzymeReplacement For the treatment of adults and children 47047 (BioMarinPharmaceuticals) Agents with Mucopolysaccharidosis VI. GefitinibTyrosine Kinase Inhibitors 447 Gemtuzumab Mylotarg ™; Mylotarg ™ (Wyeth)Antineoplastic Agents For treatment of acute myeloid leukemia 39826ozogamicin Glatiramer Acetate Copaxone ™ Adjuvants, Immunologic; Forreduction of the frequency of relapses 29914 Immunosuppressive inpatients with Relapsing-Remitting Agents Multiple Sclerosis. GlucagonGlucaGen ™ (Novo Nordisk); Antihypoglycemic Agents For treatment ofsevere hypoglycemia, 54009 recombinant Glucagon ™ (Eli Lilly) also usedin gastrointestinal imaging Goserelin Zoladex ™ Antineoplastic Agents;Breast cancer; Prostate carcinoma; 78617 Antineoplastic Agents,Endometriosis Hormonal Human Serum Albutein ™ (Alpha Therapeutic Corp)Serum substitutes For treatment of severe blood loss, 39000 Albuminhypervolemia, hypoproteinemia Hyaluronidase Vitragan ™; Vitrase ™;Vitrase ™ (Ista Anesthetic Adjuvants; For increase of absorption anddistribution 69367 Pharma) Permeabilizing Agents of other injected drugsand for rehydration Ibritumomab Zevalin ™ (IDEC Pharmaceuticals)Antineoplastic Agents For treatment of non-Hodgkin's 33078 lymphomaIdursulfase Elaprase ™ (Shire Pharmaceuticals) Enzyme Replacement Forthe treatment of Hunter syndrome in 47047 Agents adults and childrenages 5 and older. Imatinib Tyrosine Kinase Inhibitors 494 Immuneglobulin Civacir ™; Flebogamma ™ (Instituto Anti-Infectives; Fortreatment of immunodeficiencies, 42632 Grifols SA); Gamunex ™ (TalecrisImmunomodulatory Agents thrombocytopenic purpura, KawasakiBiotherapeutics) disease, gammablobulinemia, leukemia, bone transplantInfliximab Remicade ™ (Centocor Inc) Immunomodulatory For treatment ofCrohn's disease, 25645 Agents; psoriasis, rheumatoid cuminate andImmunosuppressive ankylosing spondylitis Agents Insulin GlargineLantus ™ Hypoglycemic Agents For treatment of diabetes (type I and II)156308 recombinant Insulin Lyspro Humalog ™ (Eli Lily); Insulin LisproHypoglycemic Agents For treatment of diabetes (type I and II) 154795recombinant (Eli Lily) Insulin recombinant Novolin R ™ (Novo Nordisk)Hypoglycemic Agents For treatment of diabetes (type I and II) 156308Insulin, porcine Iletin II ™ Hypoglycemic Agents For the treatment ofdiabetes (type I and 156308 II) Interferon Interferon Alfa-2a, RoferonA ™ (Hoffmann-La Roche Antineoplastic Agents; For treatment of chronichepatitis C, hairy 57759 Recombinant Inc); Veldona ™ (Amarillo AntiviralAgents cell leukemia, AIDS-related Kaposi's Biosciences) sarcoma, andchronic myelogenous leukemia. Also for the treatment of oral wartsarising from HIV infection. Interferon Alfa-2b, Intron A ™ (ScheringCorp) Antineoplastic Agents; For the treatment of hairy cell leukemia,57759 Recombinant Antiviral Agents; malignant melanoma, and AIDS-relatedImmunomodulatory Agents Kaposi's sarcoma. Interferon alfacon-1Advaferon ™; Infergen ™ (InterMune Antineoplastic Agents; For treatmentof hairy cell leukemia, 57759 Inc) Antiviral Agents; malignant melanoma,and AIDS-related Immunomodulatory Agents Kaposi's sarcoma Interferonalfa-n1 Wellferon ™ (GlaxoSmithKline) Antiviral Agents; For treatment ofvenereal or genital warts 57759 Immunomodulatory Agents caused by theHuman Papiloma Virus Interferon alfa-n3 Alferon ™ (Interferon SciencesInc.); Antineoplastic Agents; For the intralesional treatment of 57759Alferon LDO ™; Alferon N Injection ™ Antiviral Agents; refractory orrecurring external Immunomodulatory Agents condylomata cuminate.Interferon beta-1b Betaseron ™ (Chiron Corp) Antiviral Agents; Fortreatment of relapsing/remitting 57759 Immunomodulatory Agents multiplesclerosis Interferon gamma- Actimmune ™; Actimmune ™ Antiviral Agents;For treatment of Chronic granulomatous 37835 1b (InterMune Inc)Immunomodulatory Agents disease, Osteopetrosis Lapatinib Tyrosine KinaseInhibitors 581 Lepirudin Refludan ™ Anticoagulants; For the treatment ofheparin-induced 70037 Antithrombotic Agents; thrombocytopeniaFibrinolytic Agents Lestaurtinib Tyrosine Kinase Inhibitors 439Leuprolide Eligard ™ (Atrix Labs/QLT Inc) Anti-Estrogen Agents; Fortreatment of prostate cancer, 37731 Antineoplastic Agents endometriosis,uterine fibroids and premature puberty Lutropin alfa Luveris ™ (Serono)Fertility Agents For treatment of female infertility 78617 MecaserminIncrelex ™; Increlex ™ (Tercica); Iplex For the long-term treatment ofgrowth 154795 failure in pediatric patients with Primary IGFD or with GHgene deletion who have developed neutralizing antibodies to GH. It isnot indicated to treat Secondary IGFD resulting from GH deficiency,malnutrition, hypoth Menotropins Repronex ™ Fertility Agents Fortreatment of female infertility 78617 mTOR inhibitors MuromonabOrthoclone OKT3 ™ (Ortho Biotech) Immunomodulatory For treatment oforgan transplant 23148 Agents; recipients, prevention of organ rejectionImmunosuppressive Agents Natalizumab Tysabri ™ Immunomodulatory AgentsFor treatment of multiple sclerosis. 115334 Nepafenac CyclooxygenaseInhibitors Nesiritide Natrecor ™ Cardiac drugs For the intravenoustreatment of patients 118921 with acutely decompensated congestive heartfailure who have dyspnea at rest or with minimal activity. NilotinibTyrosine Kinase Inhibitors 530 NS398 Cyclooxygenase InhibitorsOctreotide Atrigel ™; Longastatin ™; Anabolic Agents; For treatment ofacromegaly and 42687 Sandostatin ™; Sandostatin LAR ™; AntineoplasticAgents, reduction of side effects from cancer Sandostatin LAR ™(Novartis) Hormonal; Gastrointestinal chemotherapy Agents; HormoneReplacement Agents Omalizumab Xolair ™ (Genentech Inc) Anti-AsthmaticAgents; For treatment of asthma caused by 29596 Immunomodulatory Agentsallergies Oprelvekin Neumega ™; Neumega ™ (Genetics Coagulants;Thrombotics Increases reduced platelet levels due to 45223 InstituteInc) chemotherapy OspA lipoprotein LYMErix ™ (SmithKline Beecham)Vaccines For prophylactic treatment of Lyme 95348 Disease OT-551(Othera) Anti-oxidant eyedrop AMD Oxytocin Oxytocin ™ (BAM Biotech);Pitocin ™ Anti-tocolytic Agents; To assist in labor, elective laborinduction, 12722 (Parke-Davis); Syntocinon ™ (Sandoz) Labor InductionAgents; uterine contraction induction Oxytocics Palifermin Kepivance ™(Amgen Inc) Antimucositis Agents For treatment of mucositis (mouthsores) 138885 Palivizumab Synagis ™ Antiviral Agents For treatment ofrespiratory diseases 63689 casued by respiratory syncytial virusPanitumumab Vectibix ™; Vectibix ™ (Amgen) Antineoplastic Agents For thetreatment of EGFR-expressing, 134279 metastatic colorectal carcinomawith disease progression on or following fluoropyrimidine-,oxaliplatin-, and irinotecan-containing chemotherapy regimens. PDGFinhibitor (Jerini Ophthalmic); (Ophthotech) Inhibitors of PDGF AMD PEDF(pigment epithelium derived factor) Pegademase Adagen ™ (Enzon Inc.)Enzyme Replacement For treatment of adenosine deaminase 36512 bovineAgents deficiency Pegaptanib Macugen ™ Oligonucleotide For the treatmentof neovascular (wet) 103121 age-related macular degeneration.Pegaspargase Oncaspar ™ (Enzon Inc) Antineoplastic Agents For treatmentof acute lymphoblastic 132.118 leukemia Pegfilgrastim Neulasta ™ (AmgenInc.) Anti-Infective Agents; Increases leukocyte production, for 28518Antineutropenic Agents; treatment in non-myeloid cancer,Immunomodulatory Agents neutropenia and bone marrow transplantPeginterferon alfa- Pegasys ™ (Hoffman-La Roche Inc) AntineoplasticAgents; For treatment of hairy cell leukemia, 57759 2a Antiviral Agents;malignant melanoma, and AIDS-related Immunomodulatory Agents Kaposi'ssarcoma. Peginterferon alfa- PEG-Intron (Schering Corp); UnitronAntineoplastic Agents; For the treatment of chronic hepatitis C in 577592b PEG ™ Antiviral Agents; patients not previously treated withImmunomodulatory Agents interferon alpha who have compensated liverdisease and are at least 18 years of age. Pegvisomant Somavert ™ (PfizerInc) Anabolic Agents; Hormone For treatment of acromegaly 71500Replacement Agents Pentoxifylline Perindozril ACE InhibitorsPimecrolimus Limus Immunophilin Binding Compounds PKC (protein kinase C)inhibitors Pramlintide Symlin ™; Symlin ™ (Amylin For the mealtimetreatment of Type I and 16988 Pharmaceuticals) Type II diabetes incombination with standard insulin therapy, in patients who have failedto achieve adequate glucose control on insulin monotherapy. ProteosomeVelcade ™ Proteosome inhibitors inhibitors Pyrrolidine Quinopril ACEInhibitors Ranibizumab Lucentis ™ For the treatment of patients with27043 neovascular (wet) age-related macular degeneration. Rapamycin(MacuSight) Limus Immunophilin AMD (siroliums) Binding CompoundsRasburicase Elitek ™; Elitek ™ (Sanofi-Synthelabo AntihyperuricemicAgents For treatment of hyperuricemia, reduces 168.11 Inc); Fasturtec ™elevated plasma uric acid levels (from chemotherapy) ReteplaseRetavase ™ (Centocor); Retavase ™ Thrombolytic Agents For lysis of acutepulmonary emboli, 54732 (Roche) intracoronary emboli and management ofmyocardial infarction Retinal stimulant Neurosolve ™ (VitreoretinalRetinal stimulants AMD Technologies) Retinoid(s) Rituximab MabThera ™;Rituxan ™ Antineoplastic Agents For treatment of B-cell non-Hodgkins33078 lymphoma (CD20 positive) RNAI (RNA interference of angiogenicfactors) Rofecoxib Vioxx ™; Ceoxx ™; Ceeoxx ™ (Merck CyclooxygenaseInhibitors & Co.) Rosiglitazone Thiazolidinediones Ruboxistaurin EliLilly Protein Kinase C (PKC)-b DME, diabetic peripheral retinopathy 469Inhibitor Salmon Calcitonin Calcimar ™; Miacalcin ™ (Novartis)Antihypocalcemic Agents; For the treatment of post-menopausal 57304Antiosteporotic Agents; osteoporosis Bone Density Conservation AgentsSargramostim Immunex ™; Leucomax ™ (Novartis); Anti-Infective Agents;For the treatment of cancer and bone 46207 Leukine ™; Leukine ™ (BerlexAntineoplastic Agents; marrow transplant Laboratories Inc)Immunomodulatory Agents SDZ-RAD Limus Immunophilin Binding CompoundsSecretin SecreFlo ™; Secremax ™, SecreFlo ™ Diagnostic Agents Fordiagnosis of pancreatic exocrine 50207 (Repligen Corp) dysfunction andgastrinoma Selective inhibitor of the factor 3 complement cascadeSelective inhibitor of the factor 5 complement cascade SemaxanibTyrosine Kinase Inhibitors 238 Sermorelin Geref ™ (Serono Pharma)Anabolic Agents; Hormone For the treatment of dwarfism, prevention 47402Replacement Agents of HIV-induced weight loss Serum albumin Megatope ™(IsoTex Diagnostics) Imaging Agents For determination of total blood and39000 iodinated plasma volumes Siroliums (MacuSight) Limus ImmunophilinAMD reformulation Binding Compounds (rapamycin) siRNAi molecule (QuarkPharmaceuticals) siRNAi molecule synthetic AMD synthetic, FTP- 801i-14Somatropin BioTropin ™ (Biotech General); Anabolic Agents; Hormone Fortreatment of dwarfism, acromegaly 71500 recombinant Genotropin ™(Pfizer); Humatrope ™ Replacement Agents and prevention of HIV-inducedweight (Eli Lilly); Norditropin ™ (Novo loss Nordisk); Nutropin ™(Genentech Inc.); NutropinAQ ™ (Genentech Inc.); Protropin ™ (GenentechInc.); Saizen ™ (Serono SA); Serostim ™; Serostim ™ (Serono SA); Tev-Tropin ™ (GATE) Squalamine Streptokinase Streptase ™ (Aventis BehringerThrombolytic Agents For the treatment of acute evolving 90569 GmbH)transmural myocardial infarction, pulmonary embolism, deep veinthrombosis, arterial thrombosis or embolism and occlusion ofarteriovenous cannulae Sunitinib Tyrosine Kinase Inhibitors 398Tacrolimus Limus Immunophilin Binding Compounds Tenecteplase TNKase ™(Genentech Inc) Thrombolytic Agents For treatment of myocardialinfarction and 54732 lysis of intracoronary emboli TeriparatideApthela ™; Forsteo ™; Forteo ™; Bone Density For the treatment ofosteoporosis in men 66361 Fortessa ™; Opthia ™; Optia ™; ConservationAgents and postmenopausal women who are at Optiah ™; Zalectra ™;Zelletra ™ high risk for having a fracture. Also used to increase bonemass in men with primary or hypogonadal osteoporosis who are at highrisk for fracture. Tetrathiomolybdate Thyrotropin Alfa Thyrogen ™(Genzyme Inc) Diagnostic Agents For detection of residueal or recurrent86831 thyroid cancer Tie-1 and Tie-2 kinase inhibitors ToceranibTyrosine Kinase Inhibitors 396 Tositumomab Bexxar ™ (Corixa Corp)Antineoplastic Agents For treatment of non-Hodgkin's 33078 lymphoma(CD20 positive, follicular) TPN 470 analogue Trastuzumab Herceptin ™(Genentech) Antineoplastic Agents For treatment of HER2-positive 137912pulmonary breast cancer Triamcinolone Triesence ™ Glucocorticoid DME,For treatment of inflammation 435 acetonide of the retina TroglitazoneThiazolidinediones Tumistatin Urofollitropin Fertinex ™ (Serono S.A.)Fertility Agents For treatment of female infertility 78296 UrokinaseAbbokinase ™; Abbokinase ™ (Abbott Thrombolytic Agents For the treatmentof ulmonary 90569 Laboratories) embolism, coronary artery thrombosis andIV catheter clearance Vandetanib Tyrosine Kinase Inhibitors 475Vasopressin Pitressin ™; Pressyn ™ Antidiuretics; Oxytocics; For thetreatment of enuresis, polyuria, 46800 Vasoconstrictor Agents diabetesinsipidus, polydipsia and oesophageal varices with bleeding VatalanibTyrosine Kinase Inhibitors 347 VEGF receptor kinase inhibitor VEGF TrapAflibercept ™ (Regneron Genetically Engineered DME, cancer, retinal veinocclusion, 96600 Pharmaceuticals, Bayer HealthCare Antibodies choroidalneovascularization, delay AG) wound healing, cancer treatment VisualCycle (Acucela) Visual Cycle Modulator AMD Modulator ACU- 4229Vitamin(s) Vitronectin receptor antagonists Volociximabe Monoclonalantibody

1. A therapeutic device to treat an eye of a patient, the eye having aposterior chamber and a sclera, the therapeutic device comprising: arigid-walled, refillable reservoir having a volume, the reservoiradapted to reside in the posterior chamber when the device is implantedin the eye; a rigid, porous structure having a plurality ofinterconnecting, irregularly shaped channels, the porous structurelocated at a distal region of the reservoir and tuned to release apredetermined rate profile of a particular therapeutic agent from thereservoir through the plurality of channels and into the posteriorchamber to treat the eye for an extended period of time; a proximal capportion positioned proximal of the reservoir and adapted to bepositioned outside the sclera when the device is implanted in the eye,the cap portion comprising a retention structure and a penetrable,non-permeable barrier to introduce the therapeutic agent into the devicewithout any need to explant the device during introduction of thetherapeutic agent into the device; and a neck portion positioned betweenthe cap portion and the reservoir portion and defined by a reducedcross-sectional dimension relative to the reservoir and the cap portion,wherein the sclera is positioned about the neck portion when the deviceis positioned in the eye.
 2. The therapeutic device of claim 1, whereinthe porous structure and reservoir chamber are tuned to release anadditional quantity of the particular therapeutic agent through theporous structure over a second extended period of time with thepredetermined release rate profile after the additional quantity of thetherapeutic agent has been introduced into the reservoir after theextended period of time.
 3. The therapeutic device of claim 1, furthercomprising an initial quantity of the particular therapeutic agentwithin the reservoir prior to implantation into the eye.
 4. Thetherapeutic device of claim 1, wherein the channels of the rigid porousstructure comprise intersecting, substantially fixed channels.
 5. Thetherapeutic device of claim 2, wherein a volume of the refillablereservoir remains substantially unchanged, the rigid porous structureremains rigid and the channels remain substantially fixed when thereservoir is pressurized with injection of therapeutic agent into thereservoir.
 6. The therapeutic device of claim 1, wherein the deviceextends along an axis so as to extend through the sclera and a choroidinto the posterior chamber, and wherein the penetrable barrier of theproximal cap portion is located on a proximal end of the reservoir so asto allow refill of the reservoir with advancement of an injection needlethrough a conjunctiva and the penetrable barrier without the needlepenetrating the sclera or choroid.
 7. The therapeutic device of claim 1,wherein at least some of the plurality of interconnecting channelsintersect at a plurality of locations.
 8. The therapeutic device ofclaim 1, wherein the rigid, porous structure comprises a sinteredmaterial.
 9. The therapeutic device of claim 1, wherein the rigid,porous structure comprises a sintered metallic disc.
 10. The therapeuticdevice of claim 1, wherein the rigid, porous structure comprises atleast one of a metal, a ceramic, and a glass.
 11. The therapeutic deviceof claim 1, wherein the rigid, porous structure comprises a thicknessand a surface area corresponding to a rate of release of the therapeuticagent over the extended time.
 12. The therapeutic device of claim 11,wherein the thickness extends between a first side and a second side ofthe structure, and wherein the plurality of interconnecting channelsextends between the first side and the second side and wherein theplurality of interconnecting channels of the rigid porous structurecomprises interconnected, substantially fixed, tortuous channels havingan effective length extending from the first side of the porousstructure to the second side of the porous structure, the effectivelength greater than the thickness of said structure.
 13. The therapeuticdevice of claim 1, wherein the interconnecting channels of the rigid,porous structure are configured to permit the therapeutic agent to passamong the interconnecting channels.
 14. The therapeutic device of claim1, wherein the rigid, porous structure comprises rigid sintered grainsof material and wherein the interconnecting channels extend at leastpartially around the rigid sintered grains of material to pass thetherapeutic agent through the porous structure.
 15. The therapeuticdevice of claim 1, wherein when implanted, the proximal cap portion isadapted to rest against and conform to a curvature of the sclera and toreside underneath a conjunctiva of the eye.
 16. The therapeutic deviceof claim 1, wherein the therapeutic agent comprises a half-life withinthe reservoir of at least about 20 days when the device is implanted,and wherein the device is adapted to remain implanted in the eye and totreat the eye with the therapeutic agent for at least about 90 days. 17.The therapeutic device of claim 1, wherein the therapeutic agentcomprises a half-life within the reservoir of at least about 30 dayswhen implanted, and wherein the device is adapted to remain implanted inthe eye and to treat the eye with the therapeutic agent for at leastabout 120 days.
 18. The therapeutic device of claim 1, wherein thereservoir comprises a volume and the rigid porous structure comprises arelease rate adapted to provide the therapeutic agent with a half-lifewithin the reservoir when implanted into the eye, the half-life withinthe reservoir substantially greater than a corresponding half-life ofthe therapeutic agent when injected directly into the vitreous and thehalf-life within the reservoir corresponding to release of therapeuticamounts for at least about 120 days.
 19. The therapeutic device of claim1, wherein the porous structure comprises a porosity, a thickness, achannel parameter and a surface area configured to release therapeuticamounts for the extended period.
 20. The therapeutic device of claim 19,wherein the channel parameter comprises a fit parameter corresponding toan effective length of interconnecting channels extending from a firstside of the porous structure to a second side of the porous structure.21. The therapeutic device of claim 20, wherein the rate of release ofthe therapeutic agent through the porous structure corresponds to aratio of the porosity to the channel parameter and wherein the ratio ofthe porosity to the channel parameter is less than about 0.5 such thatthe porous structure is capable of releasing the therapeutic agent forthe extended period.
 22. The therapeutic device of claim 1, wherein theporous structure comprises a release rate index of no more than about5.0 mm.
 23. The therapeutic device of claim 1, wherein the reservoircomprises a volume sized to contain the quantity of the therapeuticagent for release over a predetermined extended time and wherein therigid, porous structure comprises a thickness and a surface areacorresponding to a rate of release of the therapeutic agent and whereinthe volume and the rate of release correspond to a half-life of thetherapeutic agent in the reservoir.
 24. The therapeutic device of claim23, wherein the half-life corresponds substantially to a maximum rate atthe predetermined extended time so as to provide therapeuticconcentrations of the therapeutic agent.
 25. The device of claim 1,wherein the rigid porous structure comprises a first side having a firstarea, a second side having a second area corresponding substantially tothe first area, a thickness extending between the first side and thesecond side, a porosity, and a channel parameter corresponding to arelease of the therapeutic agent from the reservoir to the posteriorchamber of the eye.
 26. The therapeutic device of claim 1, wherein theparticular therapeutic agent comprises a molecular weight within a rangefrom 100 Daltons to about 1,000,000 Daltons and wherein the molecularweight corresponds to the predetermined release rate profile.
 27. Thetherapeutic device of claim 1, wherein the particular therapeutic agentcomprises one or more compounds of 2-Methoxyestradiol analogs,3-aminothalidomide, 13-cis retinoic acid, A0003, A5b1 integrininhibitor, Abarelix, Abatacept, Abciximab, ABT-578, Acetonide,Adalimumab, Aldesleukin, Alefacept, Alemtuzumab, Alpha-1-proteinaseinhibitor, Alteplase, AMG-1470, Anakinra, Anecortave acetate,Angiostatin, Anistreplase, Anti-angiogenesis peptides, Anti-angiogenesisantibodies, TRC093, TRC 105, Anti-angiogeric bifunctional protein,Anti-endothelial growth factor, Antihemophilic Factor, Antithymocyteglobulin, Anti-hypertensive MC1101, Anti-platelet devired growth factor,Anti-VEGF, AP23841, Aprotinin, Arcitumomab, Asparaginase, Axitinib,Basiliximab, Becaplermin, Bevacizumab, Bivalirudin, Bortezomib,Bosutinib, Botulinum Toxin Type A, Botulinum Toxin Type B, C5 inhibitor,Canstatin, Capromab, Captopril, CCI-779, Cediranib, Celecoxib,Cetrorelix, Cetuximab, Choriogonadotropin alfa, Cilary neurotrophicfactor, Coagulation Factor IX, Coagulation factor VIIa, Colchicines,Collagenase, Complement factor H recombinant, Compstatin derivativepeptide, POT-4, Corticotropin, Cosyntropin, Cyclophilins, Cyclosporine,Daclizumab, Darbepoetin alfa, Dasatinib, Defibrotide, Denileukindiftitox, Desmopressin, Dexamethasone, Diclofenac, Dithiocarbamate,Dornase Alfa, Drotrecogin alfa, Eculizumab, Efalizumab, Endostatin,Enfuvirtide, Epoetin alfa, Eptifibatide, Erlotinib, Etanercept,Everolimus, Exenatide, Felypressin, Fenretinide, Filgrastim,FK605-binding proteins, FKBPs, Fluocinolone Acetonide, Follitropin beta,Fumagillin, Galsulfase, Gefitinib, Gemtuzumab ozogamicin, GlatiramerAcetate, Glucagon recombinant, Goserelin, Human Serum Albumin,Hyaluronidase, Ibritumomab, Idursulfase, Imatinib, Immune globulin,Infliximab, Insulin Glargine recombinant, Insulin Lyspro recombinant,Insulin recombinant, Insulin, porcine, Interferon, Interferon Alfa-2a,Recombinant, Interferon Alfa-2b, Recombinant, Interferon alfacon-1,Interferon alfa-n1, Interferon alfa-n3, Interferon beta-1b, Interferongamma-1b, Lapatinib, Lepirudin, Lestaurtinib, Leuprolide, Lutropin alfa,Mecasermin, Menotropins, mTOR inhibitors, Muromonab, Natalizumab,Nepafenac, Nesiritide, Nilotinib, NS398, Octreotide, Omalizumab,Oprelvekin, OspA lipoprotein, OT-551, Oxytocin, Palifermin, Palivizumab,Panitumumab, PDGF inhibitor, PEDF (pigment epithelium derived factor),Pegademase bovine, Pegaptanib, Pegaspargase, Pegfilgrastim,Peginterferon alfa-2a, Peginterferon alfa-2b, Pegvisomant,Pentoxifylline, Perindozril, Pimecrolimus, PKC (protein kinase C)inhibitors, Pramlintide, Proteosome inhibitors, Pyrrolidine, Quinopril,Ranibizumab, Rapamycin (siroliums), Rasburicase, Reteplase, Retinalstimulant, Retinoid(s), Rituximab, RNAI (RNA interference of angiogenicfactors), Rofecoxib, Rosiglitazone, Ruboxistaurin, Salmon Calcitonin,Sargramostim, SDZ-RAD, Secretin, Selective inhibitor of the factor 3complement cascade, Selective inhibitor of the factor 5 complementcascade, Semaxanib, Sermorelin, Serum albumin iodinated, Siroliumsreformulation (rapamycin), siRNAi molecule synthetic, FTP-801i-14,Somatropin recombinant, Squalamine, Streptokinase, Sunitinib,Tacrolimus, Tenecteplase, Teriparatide, Tetrathiomolybdate, ThyrotropinAlfa, Tie-1 and Tie-2 kinase inhibitors, Toceranib, Tositumomab, TPN 470analogue, Trastuzumab, Triamcinolone acetonide, Troglitazone,Tumistatin, Urofollitropin, Urokinase, Vandetanib, Vasopressin,Vatalanib, VEGF receptor kinase inhibitor, VEGF Trap, Visual CycleModulator ACU-4229, Vitamin(s), Vitronectin receptor antagonists, orVolociximabe.